Benezene-fused heteroring derivatives and pharmaceutical agents comprising the same as active ingredient

ABSTRACT

A benzene-fused heteroring derivative of formula (I)                    
     wherein all symbols are the same as described in the specification, and a non-toxic salt thereof. 
     The compound of formula (I) has an inhibitory activity against cysteine protease and therefore it is useful as an agent for the prophylaxis and/or treatment of immune diseases (autoimmune diseases, infectious diseases, etc.), inflammatory diseases (inflammatory bowel diseases, multiple cerebrosclerosis, arthritis, etc.), nerve degeneration diseases (Alzheimer&#39;s disease, muscular dystrophy, etc.), bone resorption diseases (osteoporosis, etc.), respiratory system diseases, diabetes, shock, etc.

This application is a 371 of PCT/JP01/00473 filed 25 Jan. 2001.

TECHNICAL FIELD

The present invention relates to a benzene-fused heteroring derivative.

Particularly, the present invention relates to;

1) a benzene-fused heteroring derivative of formula (I)

 wherein all symbols have the same meanings as hereinafter, and anon-toxic salt thereof,

2) a method for the preparation thereof and

3) a pharmaceutical agent comprising the benzene-fused heteroringderivative and non-toxic salt thereof as active ingredient.

BACKGROUND OF THE INVENTION

Cysteine protease is a generic name of proteases which have a cysteineresidue in the activity center and catalyze protein degradation thereat.In animal cells, a large number of cysteine proteases are known; forexample, cathepsin family, calpain family, caspase-1, etc. Cysteineprotease exists in various kinds of cells extensively and plays a basicand essential role in the homeostasis, such as conversion (processing)of precursor protein into its active form and degradation of proteinswhich have become out of use, etc. Until now, its physiological effectsare being vigorously studied, and as the studies progress andcharacteristics of the enzymes are revealed, cysteine protease came tobe taken as a cause of really various kinds of diseases.

It is revealed that cathepsin S (See J. Immunol., 161, 2731 (1998)) andcathepsin L (See J. Exp. Med., 183, 1331 (1996)) play a role inprocessing of major histocompatibility antigen class-II in antigenpresenting cells which play an important role in the early stage ofimmune responses. In an experimental inflammatory response model inducedby antigens, a specific inhibitor of cathepsin S showed an inhibitoryeffect (see J. Clin. Invest., 101, 2351 (1998)). It is also reportedthat in a leishmania-infected immune response model cathepsin Binhibitor inhibited an immune response and by means of this effect itinhibited the proliferation of protozoans (See J. Immunol., 161, 2120(1998)). In vitro, a result is given that a calpain inhibitor and acysteine protease inhibitor E-64 inhibited apoptosis which is induced bystimuli on T cell receptors (see J. Exp. Med., 178, 1693 (1993)).Therefore, it is conceivable that cysteine protease is much concernedwith the progress of immune responses.

It is speculated that caspase-1 or a cysteine protease similar theretooccupies an important position in the mechanism of cell death includingapoptosis. Therefore it is expected for a cysteine protease inhibitor tobe used as an agent for the prophylaxis and/or treatment of thosediseases concerning apoptosis, such as infectious diseases,deterioration or sthenia of immune function and brain function, tumors,etc. Diseases concerning apoptosis are, acquired immune deficiencysyndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia,hairy cell leukemia, spondylopathy, respiratory apparatus disorder,arthitis, HIV or HTLV-1 related diseases such as uveitis, virus-relateddiseases such as hepatitis C, cancer, collagenosis (systemic lupuserythematosus, rheumatoid arthritis, etc.), autoimmune diseases(ulcerative colitis, Sjogren's syndrome, primary biliary cirrhosis,spontaneous thrombocytopenic purpura, autoimmune hemolytic anemia,myasthenia gravis, insulin dependent (type I) diabetes, etc.), diseasesaccompanied by thrombocytopenia (osteomyelodysplasia syndrome, periodicthrombocytopenia, aplastic anemia, spontaneous thrombocytopenia,disseminated intravascular coagulation (DIC), etc.), hepatic diseasessuch as viral hepatitis (type C, A, B, F, etc.) or hepatitismedicamentosus and cirrhosis, dementia (Alzheimer's diseases,Alzheimer's senile dementia, etc.), cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.

Moreover, caspase-1 is concerned with various inflammatory diseases andthose diseases caused by immune disorders, by means of interleukin-1β(IL-1β) production. A lot of diseases are shown to be involved withcaspase-1 including inflammatory diseases and autoimmune diseases listedbelow; inflammatory bowel diseases such as ulcerative colitis,insulin-dependent (type-I) diabetes, autoimmune thyroid diseases,infectious diseases, rejection of an organ transplantation, graft versushost diseases, psoriasis, periodontitis (above, see N. Eng. J. Med.,328, 106 (1993)), pancreatitis (see J. Interferon Cytokine Res., 17, 113(1997)), hepatitis (see J. Leuko. Biol., 58, 90 (1995)),glomerulonephritis (see Kidney Int., 47, 1303 (1995)), endocarditis (seeInfect. Immun., 64, 1638 (1996)), myocarditis (see Br. Heart J., 72, 561(1995)), systemic lupus erythematosus (see Br. J. Rheumatol., 34, 107(1995)), Hashimoto's diseases (see Autoimmunity, 16, 141 (1993)), etc.),etc. Experimentally, it is reported that in liver injury model inducedby lipopolysaccharide and D-galactosamine, a caspase-1 inhibitordepressed the symptoms, and it is expected that a caspase inhibitorshows an effect in sepsis, ischemic reperfusion and hepatitis gravis(see Am. J. Respir. Crit. Care Med., 159, 1308 (1999)).

It is also shown that cysteine protease is concerned with rheumatoidarthritis. IL-1β is shown to be concerned with this disease (seeArthritis Rheum., 39, 1092 (1996)), and in addition, as autoantibodytoward calpastatin (endogenous calpain inhibitor) was found in the serumof the patients, it is considered that increase of calpain activityleads to the cause of diseases.

It is also known that cysteine protease causes a disease symptom bydecomposing various proteins which compose the organism.

It is reported that cathepsin B plays a role in decomposing muscularprotein in the chronic phase of sepsis (see J. Clin. Invest., 97, 1610(1996)), and in decomposing muscular protein in myodystrophy model (seeBiochem. J., 288, 643 (1992)). And it is also reported that calpaindecomposes the myocyte cells protein of myodystrophy patients (see J.Biol. Chem., 270, 10909 (1995)).

In the ischemic reperfusion model, a result is given that calpain causesdegeneration of brain tissues by means of degradation of protein kinaseC-β (see J. Neurochem., 72, 2556 (1999)) and that a cathepsin Binhibitor inhibits nerve injury (see Eur. J. Neurosci., 10, 1723(1998)).

In the brain ischemic model, it is known that the degradation ofspectrin by calpain causes a damage and function disorder in theneurocyte (see Brain Res., 790, 1(1998)) and it is reported that anIL-1β receptor antagonist relieved the symptoms (see Brain Res. Bull.,29, 243 (1992)).

In myocardial ischemic model it is confirmed that cathepsin B activityincreases in the lesion (see Biochem. Med. Metab. Biol., 45, 6 (1991)).

In the experiment utilizing ischemic liver injury model, it proved thatnecrosis and apoptosis of hepacyte were induced by means ofprotein-decomposing activity of calpain (see Gastroenterology, 116, 168(1999)).

Besides, it is known that calpain causes cornea turbid in cataract bymeans of degradation of crystalline (see Biol. Chem., 268, 137 (1993))and that in the lesion of contracted gut mucosa model it was confirmedthat the activity of cathepsin B, H and L increased (see JPEN. J.Parenter. Enteral. Nutr., 19, 187 (1995)) and it is shown that cysteineprotease is a cause of the diseases resulting from such proteindegradation.

It has been revealed that cysteine protease is concerned with systemicdisorders of organs and tissues by shock.

It is shown that IL-1β is concerned with septic shock and systemicinflammatory response syndrome (see Igakuno Ayumi, 169, 850 (1994)) andbesides, it is reported that in endotoxin shock model induced bylipopolysaccharide, a calpain inhibitor prevented circulatory systemdisorder, disorders of liver and pancreas and acidosis by means ofinhibitory effect of activation of nuclear factor KB (see Br. J.Pharmacol., 121, 695 (1997)).

Since it is reported that calpain is concerned with platelet coagulationprocess and a calpain inhibitor prevented the coagulation of platelets(see Am. J. Physiol., 259, C862 (1990)), it is conceivable that acysteine protease inhibitor is useful for the disorder by bloodcoagulation. From the fact that calpain activity increased in the serumof the patients of purpura (thrombocytopenia) resulting from marrowtransplantation, it is conceivable that calpain is concerned with theactual disease symptoms (see Bone Marrow Transplant., 24, 641 (1999)).Caspase-1 inhibitor inhibited the apoptosis of blood vessel endothelialcells, which is seen in the early phase of purpura (thrombocytopenia)and is thought to be important for the progression of the pathologyafterwards (see Am. J. Hematol., 59, 279 (1998)), so it is expected thata cysteine protease inhibitor makes effect on purpura and hemolyticuremic syndrome.

The effect of cysteine protease and its inhibitor is being investigatedin the field of cancer and metastasis of cancer.

Since the proliferations of pancreas cancer cells (see Cancer Res., 59,4551 (1999)) and acute myeloid leukemia cells (see Clin. Lab. Haematol.,21, 173 (1999)) were inhibited by an inhibitor or receptor antagonist ofcaspase-1, it is expected that caspase-1 activity is essential for theprocess of proliferation of tumor cells, and that an inhibitor thereofis effective for these cancers. Cathepsin B activity increased in coloncancer metastasis model (see Clin. Exp. Metastasis, 16, 159 (1998)).Cathepsin K protein expression was recognized in human breast cancercells and the relationship of cathepsin K and bone metastasis is shown(Cancer Res., 57, 5386 (1997)). Also, a calpain inhibitor inhibitedmigaration of the cells and it implied the possibility that calpaininhibition may inhibit metastasis of cancer (J. Biochem., 272, 32719(1997)). From these, a cysteine protease inhibitor is presumed to showan inhibitory effect on the metastasis of various malignant tumors.

As to AIDS (see AIDS, 10, 1349 (1996)) and AIDS-related complex (ARC)(see Arch. Immunol. Ther. Exp. (Warsz), 41, 147 (1993)), it is shownthat IL-1 is concerned with the progress of symptoms, so it isconceivable that cysteine protease inhibition leads to an effectivetherapy of AIDS and its complication.

Some parasites have cysteine protease activity in their body. Cysteineprotease in the phagosome of malaria protozoan is an essential enzymefor supplying nutrition of the parasites. A result is given that theinhibitor of cysteine protease shows an inhibitory effect of theproliferation of the protozoan (see Blood, 87, 4448 (1996)). Thus, it ispossible to apply the inhibitor of cysteine protease to malaria.

In Alzheimer-type dementia, it is said that adhesion ofnon-physiological protein called amyloid to brain is deeply involvedwith nervous function disorders. Cysteine protease has an activity ofgenerating amyloid by decomposing its precursor protein. Clinically, itis shown that cathepsin B is an enzyme that possesses a processingactivity of amyloid proteins in the brains of Alzheimer-type dementiapatients (see Biochem. Biophys. Res. Commun., 177, 377 (1991)). Also,expressions of cathepsin B protein (see Virchows Arch. A. Pathol. Anat.Histpathol., 423, 185 (1993)), cathepsin S protein (see Am. J. Pathol.,146, 848 (1995)) and calpain protein (see Proc. Natl. Acad. Sci. USA,90, 2628 (1993)) and increase of caspase-1 activity (see J. Neuropathol.Exp. Neurol., 58, 582 (1999)) were confirmed in the brain lesions.Besides, by the fact that calpain is concerned with the formation ofpaired helical filaments which accumulate in Alzheimer dementia patientsand production of protein kinase C which stabilizes the protein byphosphorylation (see J. Neurochem., 66, 1539 (1996)) and by theknowledge that caspase is concerned with neurocyte death by β amyloidprotein adhesion (see Exp. Cell Res., 234, 507 (1997)), it is impliedthat cysteine protease is concerned with the disease symptoms.

As to Huntington's chorea, cathepsin H activity increased in thepatient's brain (see J. Neurol. Sci., 131, 65 (1995)), and the ratio ofactivated form of calpain increased (see J. Neurosci., 48, 181 (1997)).In Parkinson's diseases, the increase of expression of m-calpain wasrecognized in the mesencephalon of the patients (see Neuroscience, 73,979 (1996)) and IL-1β protein was expressed in brain (see Neurosci.Let., 202, 17 (1995)). Therefore, it is speculated that cysteineprotease is concerned with the genesis and progress of these diseases.

Besides, in the central nervous system, spectrin degradation by calpainis found in the process of injury on neurocyte observed in the traumaticbrain injury model (see J. Neuropathol. Exp. Neurol., 58, 365 (1999)).

In spinal cord injured model it was recognized that in glia cellscalpain messenger RNA increased and its activity increased in the lesionand the possibility was shown that calpain had much to do with thedegeneration of myelin and actin after injury (see Brain Res., 816, 375(1999)). And IL-1β was shown to be concerned with the genesis ofmultiple sclerosis (see Immunol. Today, 14, 260 (1993)). Therefore, itis conceivable that a cysteine protease inhibitor is promising as anagent for the treatment of these nerve-injuring diseases.

Normally, cathepsin S and cathepsin K do not exist in human arterialwalls but it was confirmed that they expressed in arterial sclerosislesion and they had an decomposing activity of alveolus elastica (see J.Clin. Invest., 102, 576 (1998)) and a calpain inhibitor and antisense ofm-calpain inhibited the proliferation of human blood vessel smoothmuscle cells and it is shown that m-calpain is concerned with theproliferation of smooth muscle (see Arteioscler. Thromb. Vssc. Biol.,18, 493 (1998)), so it is conceivable that a cysteine protease inhibitoris promising for the treatment of blood vessel lesion such asarteriosclerosis, restenosis after percutaneous transluminal coronaryangioplasty (PTCA), etc.

It is reported that in liver, cathepsin B is activated in the process ofinjuring hepatocyte by bile acid (see J. Clin. Invest., 103, 137 (1999))and so it is expected that a cysteine protease inhibitor is effectivefor cholestatic cirrhosis.

In lungs and respiratory system, it is shown that cathepsin S is anenzyme that plays a role in elastin degradation by alveolus macrophages(see J. Biol. Chem., 269, 11530 (1994)), so it is probable that cysteineprotease is a cause of pulmonary emphysema. And it is also shown thatlung injury (see J. Clin. Invest., 97, 963 (1996)), lung fibrosis (seeCytokine, 5, 57 (1993)) and bronchial asthma (see J. Immunol., 149, 3078(1992)) are caused by production of IL-1β by caspase-1.

It is pointed out that cysteine protease is also concerned with diseasesconcerning bones and cartilages. Cathepsin K is specifically recognizedin osteoclast and it has a decomposing activity against bone matrix (seeJ. Biol. Chem., 271, 12517 (1996)), so its inhibitor is expected to showan effect against osteoporosis, arthritis, rheumatoid arthritis,osteoarthritis, hypercalcemia and osteometastasis of cancer, wherepathologic bone resorption is recognized. And since IL-1β is shown to beconcerned with bone resorption and cartilage degradation, and acaspase-1 inhibitor and IL-1β receptor antagonist inhibit the boneresorption and symptoms of arthritis, a caspase-1 inhibitor and IL-1βreceptor antagonist are expected to be effective for arthritis (seeCytokine, 8, 377 (1996)) and osteoporosis (J. Clin. Invest., 93, 1959(1994)). And it is reported that IL-1β is also concerned withosteoarthritis (see Life Sci., 41, 1187 (1987)).

Cysteine protease is involved with production of various hormones. Sinceincrease of messenger RNA of cathepsin S was recognized by stimuli ofthytropin on thyroid epitheliocyte strains (see J. Biol. Chem., 267,26038 (1992)), it is conceivable that a cysteine protease inhibitor iseffective for hyperthyrodism.

Since quantity and activity of cathepsin B protein increased in thegingival sulcus liquid of periodontitis patients (see J. Clin.Periodontol., 25, 34 (1998)), it is pointed out that cysteine proteaseis concerned with periodontitis.

Therefore, it is expected that the compound that possesses theinhibitory activity of cysteine protease is useful as an agent for theprophylaxis and/or treatment of inflammatory diseases (periodontitis,arthritis, inflammatory bowel diseases, infectious diseases,pancreatitis, hepatitis, glomerulonephritis, endocarditis, myocarditis,etc.), diseases induced by apoptosis (graft versus host diseases,rejection of an organ transplantation, acquired immune deficiencysyndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia,hairy cells leukemia, spondylopathy, disorders of respiratory apparatus,arthritis, HIV or HTLV-1 related diseases such as uveitis, virus-relateddiseases such as hepatitis C, cancer, collagenosis (systemic lupuserythematosus, rheumatoid arthritis, etc.), ulcerative colitis,Sjögren's syndrome, primary biliary cirrhosis, spontaneousthrombocytopenic purpura, autoimmune hemolytic anemia, myastheniagravis, autoimmune diseases such as insulin dependent (type I) diabetes,diseases accompanying thrombocytopenia (osteomyelodysplasia syndrome,periodic thrombocytopenia, aplastic anemia, spontaneousthrombocytopenia, disseminated intravascular coagulation (DIC), etc.),hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) orhepatitis medicamentosus and cirrhosis, dementia such as Alzheimer'sdiseases and Alzheimer's senile dementia, cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.), diseases induced by disorders of immune response (graft versushost diseases, rejection of an organ transplantation, allergic diseases(bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis,diseases induced by house dusts, irritable pneumonia, food allergy,etc.), psoriasis, rheumatoid arthritis, etc.), autoimmune diseases(insulin-dependent (type I) diabetes, systemic lupus erythematosus,Hashimoto's diseases, multiple sclerosis, etc.), disease by degradationvarious proteins which compose the organism (myodystrophy, cataract,periodontitis, hepatocyte disease by bile acid such as cholestaticcirrhosis, etc.), decomposition of alveolus elastica such as pulmonaryemphysema, ischemic diseases (brain ischemia, brain disorders(encephalopathy) by ischemic reperfusion, myocardial infarction,ischemic hepatopathy, etc.), shock (septic shock, systemic inflammatoryresponse syndrome, endotoxin shock, acidosis, etc.), circulatory systemdisorders (arteriosclerosis, restenosis after percutaneous transluminalcoronary angioplasty (PTCA), etc.)), blood coagulation disorders(thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignanttumor, acquired immune deficiency syndrome (AIDS) and AIDS-relatedcomplex (ARC), parasitic diseases such as malaria, nerve degenerativediseases (Alzheimer-type dementia, Huntington's chorea, Parkinson'sdiseases, multiple sclerosis, traumatic encephalopathy, traumaticspondylopathy, etc.), pulmopathy such as lung fibrosis, bone resorptiondiseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis,hypercalcemia, osteometastasis of cancer, etc.), endocrinesthenia suchas hyperthyroidism.

On the other hand, what is the most important for inhibitors ininhibiting the activity of proteases is, the special reaction site whichinteracts with the amino acid residue that is the activity center ofproteases. The surrounding structure of the reaction sites arerepresented by - - - P3P2P1-P1′P2′P3′- - - , centering peptide binding(P1-P1′) of the reaction site, and at P1 site there exist amino acidresidues fitting the substance specificity of proteases which theinhibitors aim. Some reaction sites against cysteine proteases areknown, for Example, in the specification of WO99/54317, the followingsare described;

P1 position against calpain I, II (norvaline, phenylalanine, etc.),

P1 position against calpain I (arginine, lysine, tyrosine, valine,etc.),

P1 position against papain (homophenylalanine, arginine, etc.),

P1 position against cathepsin B (homophenylalanine, phenylalanine,tyrosine, etc.),

P1 position against cathepsin S (valine, norleucine, phenylalanine,etc.),

P1 position against cathepsin L (homophenylalanine, lysine, etc.),

P1 position against cathepsin K (arginine, homophenylalanine, leucine,etc.),

P1 position against caspase (aspartic acid).

On the other hand, in the specification of JP-A-6-192199, it isdisclosed that a ketone derivative of formula (A) is effective as athiol protease inhibitor,

wherein R^(1A) is hydrogen, R^(10A)—CO—, R^(10A)—OCO—, R^(10A)—SO₂— orR^(10A)—NHCO—,

(1) when AA is —S—, —SO— or —SO₂, R^(9A) is C6-C14 aryl optionallycontaining substituent(s) or —(CH₂)_(m) ^(A)—X^(A), wherein X^(A) ishydrogen, hydroxy, C1-C5 alkylthio, C2-C6 alkoxycarbonylamino,heterocycle residue optionally containing substituent(s), amino, C1-C5monoalkylamino, C2-C10 dialkylamino, C2-6 acylamino, halogen, C1-C5alkoxy, C6-C14 aryl optionally containing substituent(s) or C6-C14aryloxy optionally containing substituent(s), and m^(A) is an integer of0 or 1 to 15,

(2) when A^(A) is —O—, R^(9A) is hydrogen or —(CH₂)_(IA)—X^(A), whereinI^(A) is an integer of 1 to 15,

(3) when A^(A) is —NR^(11A)—, R^(9A) is C6-C14 aryl optionallycontaining substituent(s), —(CH₂)_(m) ^(A)—X^(A), R^(9A) and R^(11A) aretaken together to form an N-containing heteroring optionally containingsubstituent(s) (the essential parts are extracted to explainsubstituents).

And in the specification of JP-A-7-70058, it is disclosed thatα-aminoketone derivative of formula (B)

or its pharmaceutically acceptable salt shows a strong inhibitoryactivity against thiol protease, wherein R^(1B) is hydrogen,R^(4B)—O—C(O)— or R^(4B)—C(O)—, wherein R^(4B) is C1-C20 alkyloptionally containing a substituent or more selected from C3-C15cycloalkyl, C6-C14 aryl optionally containing substituent(s),heterocycle residue optionally containing substituent(s), C3-C15cycloalkyloxy, C6-C14 aryloxy optionally containing substituent(s),aralkyloxy optionally containing substituent and C6-C14 arylthiooptionally containing substituent(s); C2-C10 alkenyl optionallysubstituted with C6-C14 aryl optionally containing substituent(s);C6-C14 aryl optionally containing substituent(s) or heterocycle residueoptionally containing substituent), R^(2B) and R^(3B) are eachindependently, hydrogen or C1-C20 alkyl optionally containing asubstituent,

is heterocycle residue optionally containing a substituent, n^(B) is 0or 1, m^(B) is an integer of 1 to 5.

DISCLOSURE OF THE INVENTION

The present inventors have energetically investigated to find out suchcompounds that have cysteine protease inhibitory activity and found thatthe benzene-fused heteroring derivative of formula (I) of the presentinvention accomplishes the purpose.

The benzene-fused heteroring of formula (I) of the present invention isnot known at all as a cysteine protease inhibitor at all.

The present invention relates to

(1) an oxadiazole derivative of formula (I),

wherein R is

(i) hydrogen,

(ii) C1-8 alkyl,

(iii) CycA,

(iv) C1-8 alkyl substituted with a group selected from halogen atom,CycA, nitro, CF₃ and cyano,

CycA is a C3-15 mono-, bi- or tri-cyclic carboring or a mono-, bi- ortri-cyclic 3-15 membered heteroring comprising 1-4 of nitrogen, 1-2 ofoxygen and/or 1 of sulfur;

R¹⁶ is

(1) C1-8 alkyl,

(2) C2-8 alkenyl,

(3) C2-8 alkynyl,

(4) CycA or

(5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with a groupselected from halogen atom, nitro, CF₃, cyano, CycA, NR¹⁸R¹⁹ and—NHC(O)-CycA;

R¹⁷, R¹⁸ and R¹⁹ each independently represents hydrogen or C1-4 alkyl,

AA¹ is

(i) a single bond, or

wherein R¹ and R² are the same or different to represent

(i) hydrogen,

(ii) C1-8 alkyl,

(iii) CycA or

(iv) C1-8 alkyl substituted with 1-5 of group selected from thefollowing (1) to (8):

(1) —NR² ¹R² ²,

(2) —O² ³,

(3) —SR² ⁴,

(4) —COR² ⁵,

(5) —NR² ⁶CONR² ¹R² ²,

(6) guanidino,

(7) CycA,

(8) —NR² ⁶SO₂R² ¹; or

R¹ and R² are taken together to form C2-8 alkylene, wherein one carbonatom may be replaced by oxygen, sulfur or —NR²⁰— and the alkylene may besubstituted with —NR²¹R²² or —OR²³,

R²⁰ is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkylsubstituted with phenyl,

R²¹, R²², R²³, R²⁴ and R²⁶ are the same or different to representhydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

R²⁵ is C1-4 alkyl, phenyl, —NR²¹R²², wherein all symbols have the samemeaning as above, —OR²³, wherein R²³ is the same meaning as above, orC1-4 alkyl substituted with phenyl,

R³ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenylor

R³ is taken together with R¹ to form C2-6 alkylene, wherein one carbonatom may be replaced by oxygen, sulfur or —NR²⁰— and the alkylene may besubstituted with —NR²¹R²² or —OR²³, or when AA¹ is

AA¹ and R may be taken together to form

is a 5-12 membered mono- or bi-cyclic heteroring and the other symbolsare the same meanings as above,

AA² is

(i) a single bond,

wherein R⁴ and R⁵ are the same or different to represent

(1) hydrogen,

(2) C1-8 alkyl,

(3) CycA or

(4) C1-8 alkyl substituted with 1-5 of group selected from the following(a) to (h):

(a) —NR⁴ ¹R⁴ ²,

(b) —OR⁴ ³,

(c) —SR⁴ ⁴,

(d) —COR⁴ ⁵,

(e) —NR⁴ ⁶CONR⁴ ¹R⁴ ²,

(f) guanidino,

(g) CycA,

(h) —NR⁴ ⁶SO₂R⁴ ¹; or

R⁴ and R⁵ are taken together to form C2-8 alkylene, wherein one carbonatom may be replaced by oxygen, sulfur or —NR⁴⁰— and the alkylene may besubstituted with —NR⁴¹R⁴² or —OR⁴³,

R⁴⁰ is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkylsubstituted with phenyl,

R⁴¹, R⁴², R⁴³, R⁴⁴ and R⁴⁶ are the same or different to representhydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

R⁴⁵ is C1-4 alkyl, phenyl, —NR⁴¹R⁴², wherein all symbols are the samemeaning as above, —OR⁴³, wherein R⁴³ is the same meaning as above, orC1-4 alkyl substituted with phenyl,

R⁶ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenylor

R⁶ is taken together with R⁴ to form C2-6 alkylene, wherein one carbonatom may be replaced by oxygen, sulfur or —NR⁴⁰— and the alkylene may besubstituted with —NR⁴¹R⁴² or —OR⁴³,

R⁴⁸ is hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted withphenyl or when AA¹ is a single bond, R⁴⁸ and R may be taken together toform C2-6 alkylene, wherein one carbon atom may be replaced by oxygen,sulfur or —NR⁴⁷, wherein R⁴⁷ is hydrogen or C1-4 alkyl,

CycC is a 3-17 membered mono- or bi-cyclic heteroring,

CycD is a C3-14 mono- or bi-cyclic carboring or a 3-14 membered mono- orbi-cyclic heteroring, or

AA² and AA¹ are taken together to form

wherein

CycE is a 4-18 membered mono- or bi-cyclic heteroring,

CycF is a 5-8 membered monocyclic heteroring, and the other symbols havethe same meanings as above,

R⁷ and R⁸ are the same or different to represent

(i) hydrogen,

(ii) C1-8 alkyl,

(iii) CycA or

(iv) C1-8 alkyl substituted with 1-5 of group selected from thefollowing (1) to (8);

(1) —NR⁶¹R⁶²,

(2) —OR⁶³,

(3) —SR⁶⁴,

(4) —COR⁶⁵,

(5) —NR⁶⁶CONR⁶¹R⁶²,

(6) guanidino,

(7) CycA,

(8) —NR⁶⁶SO₂R⁶¹, or

R⁷ and R⁸ are taken together to form C2-8 alkylene, wherein one carbonatom may be replaced by oxygen, sulfur or —NR⁶⁰— and the alkylene may besubstituted with —NR⁶¹R⁶² or —OR⁶³,

R⁶⁰ is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkylsubstituted with phenyl,

R⁶¹, R⁶², R⁶³, R⁶⁴ and R⁶⁶ are the same or different to representhydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

R⁶⁵ is C1-4 alkyl, phenyl, —NR⁶¹R⁶², wherein all symbols are the samemeanings as above, —OR⁶³, wherein R⁶³ is the same meaning as above, orC1-4 alkyl substituted with phenyl,

R⁹ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenylor

R⁹ is taken together with R⁷ to form C2-6 alkylene, wherein one carbonatom may be replaced by oxygen, sulfur or —NR⁶⁰— and the alkylene may besubstituted with —NR⁶¹R⁶² or —OR⁶³,

r is an integer of 1 to 4,

in the ring of (i), (ii) and (iii), one saturated carbon atom or two maybe replaced by

(1) oxygen,

(2) —S(O)_(s)— or

(3) —NR⁸³—,

wherein s is 0 or an integer of 1 to 2,

R⁸³ is

(a) hydrogen,

(b) C1-8 alkyl,

(c) CycA or

(d) C1-8 alkyl substituted with 1-5 of group selected from CycA,guanidino, —COR⁶⁸, —NR⁶⁹R⁷⁰, —OR⁶⁹, cyano and —P(O)(OR⁷⁵)₂,

R⁶⁸ is C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

R⁶⁹ and R⁷⁰ are the same or different to represent hydrogen, C1-4 alkyl,phenyl or C1-4 alkyl substituted with phenyl,

R⁷⁵ is hydrogen, C1-8 alkyl, phenyl or C1-4 alkyl substituted with 1-5of phenyl, cyano or halogen atom and the ring of (i), (ii) and (iii) maybe condensed with a C5-C8 carbon ring or a 5-8 membered heteroringcontaining one nitrogen atom or two, one oxygen atom and/or a sulfuratom,

q is an integer of 0 or 1 to 5,

R¹⁰ is

(i) C1-8 alkyl,

(ii) C2-8 alkenyl,

(iii) C2-8 alkynyl,

(iv) halogen atom,

(v) CycA,

(vi) —COR⁷¹,

(vii) —NR⁷²R⁷³,

(viii) —OR⁷⁴ or

(ix) C1-8 alkyl substituted with 1 to 5 of groups selected from thefollowing <1> to <7>:

<1> CycA,

<2> guanidino,

<3> —COR⁷¹,

<4> —NR⁷²R⁷³,

<5> —OR⁷⁴,

<6> cyano or

<7> —P(O)(OR⁷⁸)₂,

wherein R⁸² is hydrogen, C1-8 alkyl, phenyl or C1-4 alkyl substitutedwith 1 to 5 of phenyl, cyano or halogen atom,

R⁷¹ is

(1) C1-8 alkyl,

(2) CycA,

(3) —NR⁷²R⁷³,

(4) —OR⁷⁴, or

(5) C1-8 alkyl substituted with CycA;

R⁷² and R⁷³ are the same or different to represent

(1) hydrogen,

(2) C1-8 alkyl,

(3) CycA or

(4) C1-8 alkyl substituted with 1 to 5 of groups selected from thefollowing (a) to (f):

(a) CycA,

(b) guanidino,

(c) —NR⁷⁷R⁷⁸, wherein R⁷⁷ and R⁷⁸ have the same or different torepresent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted withphenyl,

(d) —OR⁷⁷, wherein R⁷⁷ has the same meaning as above,

(e) —COR⁷⁶, wherein R⁷⁶ has C1-4 alkyl, phenyl, —NR⁷⁷R⁷⁸, wherein allsymbols have the same meanings as above, —OR⁷⁷, wherein R⁷⁷ has the samemeaning as above, or C1-4 alkyl substituted with phenyl, and

(f) cyano;

R⁷⁴ is

(1) hydrogen,

(2) C1-8 alkyl,

(3) CycA, or

(4) C1-8 alkyl substituted with 1 to 5 of groups selected from thefollowing (a) to (h), wherein one carbon atom may be replaced by oxygen,sulfur atom or —NR⁸⁴:

(a) CycA,

(b) guanidino,

(c) —SiR⁷⁹R⁸⁰R⁸¹, wherein R⁷⁹, R⁸⁰ and R⁸¹ are the same or different torepresent C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl,

(d) —NR⁷⁷R⁷⁸, wherein all symbols have the same meanings as above,

(e) —OR⁷⁷, wherein R⁷⁷ has the same meaning as above,

(f) —COR⁷⁶, wherein R⁷⁶ has the same meaning as above,

(g) cyano,

(h) —P(O)(OR⁸²)₂, wherein all symbols have the same meaning as above;

CycA included in R, R¹, R², R⁴, R⁵, R⁷, R⁸, R¹⁰, R¹⁶, R⁷¹, R⁷², R⁷³, R⁷⁴and R⁸³ are the same or different and CycA, CycB, CycC, CycD, CycE andCycF, independently, may be substituted with 1 to 5 of R²⁷;

R²⁷ is

(1) C1-8 alkyl,

(2) halogen atom,

(3) —NR¹¹R¹²,

(4) —OR¹³,

(5) a C5-10 mono-or bi-cyclic carboring,

(6) nitro,

(7) CF₃,

(8) cyano,

(9) a 5-10 membered mono- or bi-cyclic heteroring

(10) —SR¹⁴,

(11) —COR¹⁵,

(12) oxo,

(13) —SO₂R¹⁵,

(14) —OCF₃ or

(15) C1-8 alkyl substituted with 1-5 of group selected from thefollowing (a) to (m)

(a) halogen atom,

(b) —NR¹¹R¹²,

(c) —OR¹³,

(d) a C5-10 mono- or bi-cyclic carboring,

(e) nitro,

(f) CF₃,

(g) cyano,

(h) a 5-10 membered mono- or bi-cyclic heteroring,

(j) —SR¹⁴,

(k) —COR¹⁵,

(l) —SO₂R¹⁵,

(m) —OCF₃,

wherein

R¹¹ and R¹² are the same or different to represent hydrogen, C1-4 alkyl,—COO—(C1-4 alkyl), phenyl or C1-4 alkyl substituted with phenyl,

R¹³ and R¹⁴ are the same or different to represent hydrogen, C1-4 alkyl,phenyl or C1-4 alkyl substituted with phenyl,

R¹⁵ is C1-4 alkyl, phenyl, —NR¹¹R¹², wherein all symbols have the samemeanings as above, —OR¹³, wherein R¹³ is the same meaning as above, orC1-4 alkyl substituted with phenyl, or a non-toxic salt thereof,

(2) a method for the preparation thereof and

(3) a pharmaceutical agent comprising the benzene-fused heteroringderivative and non-toxic salt thereof as active ingredient.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the compound of formula (I), in

which AA¹ and R together form,

is a 5-12 membered heteroring containing 1-3 of nitrogen, 1 of oxygen,and/or 1 of sulfur (this heteroring may be substituted with 1-5 of R²⁷).

And to describe

concretely, it is

wherein J¹ is oxygen, sulfur, —NR²⁹—, wherein R²⁹ is hydrogen, C1-4alkyl, CycA or C1-4 alkyl substituted with CycA, C1-3 alkylene or C2-3alkenylene,

J² is a single bond or C1-2 alkylene,

Y² is —N═CH—, —CH═N— or C1-2 alkylene,

J³ is carbonyl or C1-3 alkylene,

Y³ is C1-3 alkylene, oxygen or —NR²⁹—, wherein R²⁹ is the same meaningas above,

R²⁸ is hydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with CycA,or

R²⁸ is taken together with R¹to form C2-4 alkylene, and the othersymbols have the same meaning as above and each ring may be substitutedwith 1-5 of R²⁷.

In the compound of formula (I), in

which AA² represents, CycC is a 3-17 membered heteroring which contains1-2 of nitrogen, 1 of oxygen and/or 1 of sulfur (this ring may besubstituted with 1-5 of R²⁷).

And to describe

concretely,

wherein J⁴, Y⁴ and L⁴ are the same or different to represent a singlebond or C1-3 alkylene, wherein J⁴, Y⁴ and L⁴ do not represent a singlebond at the same time,

J⁵ is C1-6 alkylene,

Y⁵ is a single bond, C1-3 alkylene or —NR⁶⁷—, wherein R⁶⁷ is hydrogen,C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

J⁸ is C1-5 alkylene, wherein one carbon atom may be replaced by oxygen,

Y⁸ is a single bond or C1-4 alkylene,

L⁸ is —N— or —CH—,

and the other symbols have the same meaning as above and each ring maybe substituted with 1-5 of R²⁷.

And in

which AA² represents, CycD is a C3-14 mono- or bi-cyclic carboring or3-14 membered heteroring which contains 1-2 of nitrogen, 1 of oxygenand/or 1 of sulfur (this carboring and heteroring may be substitutedwith 1-5 of R²⁷).

And to describe

concretely, it is

wherein J⁶ and Y⁶ are the same or different to represent a single bondor C1-3 alkylene, wherein J⁶ and Y⁶ do not represent a single bond atthe same time,

J⁷ is C1-6 alkylene, wherein one carbon atom may be replaced by oxygen,sulfur or —NR⁶⁷—, wherein R⁶⁷ has the same meaning as above,

J⁹ is C1-3 alkylene, oxygen, sulfur or —NR⁶⁷—, wherein R⁶⁷ is the samemeaning as above,

and the other symbols have the same meanings as above and each ring maybe replaced by 1-5 of R²⁷.

In the compounds of the formula (I), in

which AA¹ and AA² together form,

CycE is a 4-18 membered heteroring which contains 1-2 of nitrogen, 1 ofoxygen and/or 1 of —S(O)_(p)— (this heteroring may be substituted with1-5 of R²⁷).

And to describe

concretely, it is

wherein

is a single bond or a double-bond,

J¹⁰ and Y¹⁰ are the same or different to represent a single bond or C1-3alkylene,

L¹⁰ is a single bond, C1-3 alkylene, —NR⁵⁷—, wherein R⁵⁷ is hydrogen,C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl, —N═, oxygen or—S(O)_(p)—, wherein p is 0 or an integer of 1 to 2,

J¹² and Y¹² are the same or different to represent a single bond or C1-3alkylene,

L¹² is C1-3 alkylene, —NR⁵⁷—, wherein R⁵⁷ is the same meaning as above),—N═, ═N—, oxygen or —S(O)_(p)—, wherein p has the same meaning as above,

and the other symbols have the same meanings as above and each ring maybe substituted with 1-5 of R²⁷.

And in

which AA¹ and AA² together form,

CycF is a 5-8 membered heteroring containing 2 of nitrogen.

And to describe

concretely, it is

wherein J¹¹ is carbonyl or C2-4 alkylene and the other symbols have thesame meaning as above and the ring therein may be substituted with 1-5of R²⁷.

In the present specification, C1-4 alkyl is methyl, ethyl, propyl, butyland isomers thereof.

In the present specification, C1-8 alkyl is methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.

In the present specification, C2-8 alkenyl is, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl containing 1-3 of double bond and isomersthereof. For example, vinyl, propenyl, butenyl, hexenyl, hexadienyl,octadienyl, etc. are included.

In the present specification, C2-8 alkynyl is ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl containing 1-3 of triple bond and isomersthereof. For example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, etc. are included.

In the present specification, C1-4 alkyl substituted with phenyl isphenylmethyl, phenylethyl, phenylpropyl, phenylbutyl and isomersthereof.

In the present specification, C1-8 alkyl substituted with phenyl isphenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl,phenylhexyl, phenylheptyl, phenyloctyl and isomers thereof.

In the present specification, C1-2 alkylene is, methylene, ethylene andisomers thereof.

In the present specification, C1-3 alkylene is, methylene, ethylene,trimethylene and isomers thereof.

In the present specification, C1-4 alkylene is methylene, ethylene,trimethylene, tetramethylene and isomers thereof.

In the present specification, C1-5 alkylene is methylene, ethylene,trimethylene, tetramethylene, pentamethylene and isomers thereof

In the present specification, C1-6 alkylene is methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene and isomersthereof.

In the present specification, C2-4 alkylene is ethylene, trimethylene,tetramethylene and isomers thereof.

In the present specification, C2-6 alkylene is ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene and isomers thereof.

In the present specification, C2-8 alkylene is ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, heptamethylene,octamethylene and isomers thereof.

In the present specification, C2-6 alkylene whose one carbon atom may bereplaced by oxygen, sulfur, —NR²⁰—, —NR⁴⁰— or —NR⁶⁰— is ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene and isomersthereof, wherein one carbon atom thereof may be replaced by oxygen,sulfur, —NR²⁰—, —NR⁴⁰—, or —NR⁶⁰—, for example, such groups are—CH₂—O—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—S—CH₂—, —CH₂—CH₂—NH—CH₂—,—CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—S—CH₂—CH₂—, —CH₂—CH₂—NH—CH₂—CH₂—,—CH₂—CH₂—N(CH₃)—CH₂—CH₂—, etc.

In the present specification, C2-8 alkylene whose one carbon atom may bereplaced by oxygen, sulfur, —NR²⁰—, —NR⁴⁰— or —NR⁶⁰— is ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene and isomers thereof, wherein one carbonatom may be replaced by oxygen, sulfur, —NR²⁰—, —NR⁴⁰— or —NR⁶⁰—, forexample, such groups are —CH₂—O—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—S—CH₂—,—CH₂—CH₂—NH—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—S—CH₂—CH₂—,—CH₂—CH₂—NH—CH₂—CH₂—, —CH₂—CH₂—N(CH₃) —CH₂—CH₂—, etc.

In the present specification, C2-3 alkenylene means vinylene andallylene and isomers thereof.

In the present specification, C1-4 alkoxy is methoxy, ethoxy, propoxy,butoxy and isomers thereof.

In the present specification, C3-6 alkylene is trimethylene,tetramethylene, pentamethylene, hexamethylene and isomers thereof.

In the present specification, halogen atom means chlorine, fluorine,bromine and iodine atom.

In the present specification, mono- or bi-cyclic C5-10 carboring ismono- or bi-cyclic C5-10 carboaryl or partially or completely saturatedone thereof. For example, cyclopentane, cyclohexane, cycloheptane,cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene,pentalene, indene, naphthalene, azulene, perhydropentalene,perhydroindene, perhydronaphthalene, perhydroazulene, adamantyl ring,etc. are included.

In the present specification, mono-, bi- or tri-cyclic C3-15 carboringis mono-, bi- or tri-cyclic carboaryl or partially or completelysaturated one thereof. For example, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene,cyclopentadiene, cyclohexadiene, benzene, pentalene, indene,naphthalene, azulene, fluorene, phenanthrene, anthracene,acenaphthylene, biphenylene, perhydropentalene, perhydroindene,perhydronaphthalene, perhydroazulene, perhydrofluorene,perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene,perhydrobiphenylene, adamantyl ring etc. are included.

In the present specification, mono- or bi-cyclic 5-10 memberedheteroring containing 1-4 of nitrogen, 1 of oxygen and/or sulfur ismono- or bi-cyclic 5-10 membered heteroaryl containing 1-4 of nitrogen,1 of oxygen and/or sulfur or partially or completely saturated onethereof.

Above 5-10 membered mono- or bi-cyclic heteroaryl containing 1-4 ofnitrogen, 1 of oxygen and/or 1 of sulfur is, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyrane, oxepine,thiophene, thiaine (thiopyrane), thiepine, oxazole, isooxazole,thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzothiazole, benzoimidazole, etc.

Above partially or completely saturated mono- or bi-cyclic 5-10 memberedheteroaryl containing 1-4 of nitrogen, 1 of oxygen and/or 1 of sulfuris, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, piperidine, piperazine, tetrahydropyridine,tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran,tetrahydrofuran, dihydropyrane, tetrahydropyrane, dihydrothiophene,tetrahydrothiophene, dihydrothiaine (dihydrothiopyrane),tetrahydrothiaine (tetrahydrothiopyrane), oxazoline (dihydrooxazole),oxazolidine (tetrahydroxazole), dihydroisoxazole, tetrahydroisoxazole,oxadiazoline (dihydroxadiazole), oxadiazolidine (tetrahydroxadiazole),thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole),dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine,indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole,etc.

In the present specification, a 3-15 membered mono-, bi- or tri-cyclicheteroring containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfuris 3-15 membered mono-, bi- or tri-cyclic heteroaryl containing 1-4 ofnitrogen, 1-2 of oxygen and/or 1 of sulfur or partially or completelysaturated one thereof.

Above 3-15 membered mono-, bi- or tri-cyclic heteroring containing 1-4of nitrogen, 1-2 of oxygen and/or 1 of sulfur is, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyrane, oxepine,oxazepine, thiophene, thiaine (thiopyrane), thiepine, oxazole,isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzoxadiazole, benzothiazole, benzoimidazole, carbazole,acridine ring, etc. Above partially or completely saturated mono-, bi-or tri-cyclic 3-15 membered heteroring containing 1-4 of nitrogen, 1-2of oxygen and/or 1 of sulfur is, aziridine, oxirane, azetidine, oxetane,thiirane, thietane, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, piperidine, piperazine, tetrahydropyridine,tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran,tetrahydrofuran, dihydropyrane, tetrahydropyrane, dihydrothiophene,tetrahydrothiophene, dihydrothiaine (dihydrothiopyrane),tetrahydrothiaine (tetrahydrothiopyrane), oxazoline (dihydroxazole),oxazolidine (tetrahydroxazole), dihydroisoxazole, tetrahydroisoxazole,oxadiazoline (dihydroxadiazole), oxadiazolidine (tetrahydroxadiazole),thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole),dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine,indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole,benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, indoloxazepine, indolotetrahydroxazepine,indoloxadiazepine, indolotetrahydroxadiazepine, indolothiazepine,indolotetrahydrothiazepine, indolothiadiazepine,indolotetrahydrothiadiazepine, indolazepine, indolotetrahydroazepine,indolodiazepine, indolotetrahydrodiazepine, benzofurazane,benzothiadiazole, benzotriazole, camphor, imidazothiazole,dihydrocarbazole, tetrahydrocarbazolei, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine, dioxolane,dioxane, dioxazine ring etc.

In the present specification, C5-8 carboring is C5-8 mono-cycliccarboaryl or partially or completely saturated one thereof. For example,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene,cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, cycloheptatriene,cyclooctatriene, etc. are included.

In the present specification, 5-8 membered heteroring containing 1 or 2of nitrogen, 1 of oxygen and/or 1 of sulfur is, mono-cyclic 5-8 memberedheteroaryl containing 1 or 2 of nitrogen, 1 of oxygen and/or 1 ofsulfur, or partially or completely saturated one thereof. For example,pyridine, piperidine, pyrrole, pyrrolidine, azepine, hexahydroazepine,diazepine, furan, dioxane, dioxole, pyran, oxepine, oxocine, thiophene,thiane, thiepine, oxathiolane, oxazolidine, pyrazole, oxazole, pyrazine,pyrimidine, pyridazine, etc. are included.

In the present specification, a 5-12 membered heteroring containing 1-3of nitrogen, 1 of oxygen and/or 1 of sulfur atom, i.e.

is, for example, a ring represented by

Specifically, 2-oxo-1,3,4-triazoline, 5-oxo-1,2,4-oxadiazoline,5-oxo-1,2,4-thiadiazoline, 4-oxoimidazoline,3,4-dihydro-4-oxopyrimidine, 3,4,5,6-tetrahydro-4-oxopyrimidine,2-oxoindoline, 2-oxo-tetrahydroquinoline, 1,2-dihydro-2-oxoquinazoline,1,2-dihydro-2-oxoquinoxaline, 3-oxopyrazolidine,perhydro-3-oxopyridazine, 2-oxo-1,3,4-oxadiazolidine,perhydro-2-oxo-1,3,4-oxadiazine, etc. are included.

In the specification, 3-17 membered heteroring containing 1-2 ofnitrogen, 1 of oxygen and/or 1 of sulfur represented by CycC is, forexample, a ring represented by

Specifically, pyrrolidine, imidazolidine, pyrazolidine, piperidine,piperazine, perhydropyrimidine, perhydropyridazine, thiazolidine,indoline, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, etc.are included.

In the specification, a C3-14 mono- or bi-cyclic carboring or 3-14membered heteroring containing 1-2 of nitrogen, 1 of oxygen, and/or 1 ofsulfur represented by CycD is, for example, a ring represented by

Specifically, cyclopentane, cyclohexane, cycloheptane, benzene, indan,tetrahydronaphthalene, oxorane, oxane, thiorane, thian, pyrrolidine,piperidine, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,7-azabicyclo[2.2.1]heptane, 7-oxobicyclo[2.2.1]heptane,7-thiabicyclo[2.2.1]heptane, etc. are included.

In the specification, 4-18 membered heteroring containing 1-2 ofnitrogen, 1 of oxygen and/or 1 of —S(O)_(p)—, i.e. CycE is, for example,a ring represented by

Specifically, 2-oxopyrrolidine, 2-oxopiperidine, 2-oxoperhydroazepine,2-oxopiperazine, 3-oxomorpholine, 1,1,-dioxo-3-isothiazolidine,1,1-dioxo-3-isothiazine, 4-oxodiazepine, 2-oxoindoline,2-oxo-tetrahydroquinoline, 1,1-dioxo-3-benzisothiazolidine,1,1-dioxo-3-benzisothiazine, etc. are included.

In the present invention, 5-8 membered heteroring which contains 2 ofnitrogen. i.e. CycF is, for example, a ring represented by

Specifically, 2,4-dioxoimidazolidine, 2-oxopiperazine,2-oxoperhydrodiazepine substituted by R¹ and R² are included.

In the present invention, as may be easily understood by those skilledin the art, the symbol:

indicates that the substituent attached thereto is in front of the sheet(β-position) unless specified,

indicates that the substituent attached thereto is behind the sheet(α-position) unless specified, and

indicates that the substituent attached thereto is in β-position orα-position or a mixture thereof.

In the formula (I), all groups represented by R are preferable, butpreferably, R is

(i) hydrogen,

(ii) C1-8 alkyl,

(iii) CycA,

(iv) C1-8 alkyl substituted with a group selected from CycA and nitro,

more preferably, C1-8 alkyl or C1-8 alkyl substituted with CycA ornitro, or

Any group represented by R¹⁶ is preferable, but more preferably, R¹⁶ is

[I] (1) C1-8 alkyl,

(2) C2-8 alkenyl,

(3) C2-8 alkynyl,

(4) CycA, or

(5) C1-8 alkyl substituted with a group selected from CycA or—NHC(O)-CycA,

(6) C2-8 alkenyl substituted with CycA or

(7) C2-8 alkynyl substituted with CycA,

wherein CycA may be substituted with 1-5 of R^(27a), and

R^(27a), is (1) C1-8 alkyl,

(2) halogen,

(3) —NR¹¹R¹²,

(4) —OR¹³,

(5) phenyl,

(6) nitro,

(7) CF₃,

(8) cyano,

(9) tetrazole,

(10) —SR¹⁴,

(11) —COR¹⁵,

(12) oxo or

(13) C1-8 alkyl substituted with 1-5 of group selected from thefollowing (a) to (k):

(a) halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) phenyl, (e) nitro, (f) CF₃,(g) cyano, (h) tetrazole, (j) —SR¹⁴, (k) —COR¹⁵, or

[II] (a) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with agroup selected from halogen, CF₃, nitro, cyano or NR¹⁸R¹⁹ or

(b) (1) CycA containing 1-5 of substituent R²⁷ or

(2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with CycA,which contains 1-5 of substituent R²⁷,

wherein at least one of R²⁷ described in (1) and (2) is selected from

(i) a C5-10 mono- or bi-cyclic carboring,

(ii) a 5-10 membered mono- or bi-cyclic heteroring,

(iii) —SO₂R¹⁵, (iv) —OCF₃ or

(v) C1-8 alkyl substituted with 1-5 of the group selected from (a)halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) a C5-10 mono-or bi-cycliccarboring, (e) nitro, (f) CF₃, (g) cyano, (h) a 5-10 membered mono- orbi-cyclic heteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵ and (m) —OCF₃(at least one is a C5-10 mono-or bi-cyclic carboring, a 5-10 mono- orbi-cyclic heteroring, —SO₂R¹⁵ or —OCF₃))

Particularly preferably,

[I] (1) C1-8 alkyl,

(2) C2-8 alkenyl,

(3) C2-8 alkynyl,

(4) CycA or

(5) C1-8 alkyl substituted with a group selected from CycA or—NHC(O)-CycA,

(6) C2-8 alkenyl substituted with CycA or

(7) C2-8 alkynyl substituted with CycA,

wherein CycA is a mono- or bi-cyclic C5-10 carboaryl which may besubstituted with 1-5 of R²⁷ or partially or completely saturated onethereof, or mono- or bi-cyclic 5-10 membered heteroaryl containing 1-2of nitrogen, 1-2 of oxygen and/or 1 of sulfur atom, or partially orcompletely saturated one thereof or

[II] (a) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with agroup selected from halogen atom, CF₃, nitro, cyano and NR¹⁸R¹⁹, or

(b) CycA containing 1-5 of substituent R²⁷ or

(2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with CycA,which contains 1-5 of substituent R²⁷,

wherein at least one of R²⁷ described in (1) and (2) is selected from

(i) a C5-10 mono- or bi-cyclic carboring,

(ii) a 5-10 membered mono- or bi-cyclic heteroring,

(iii) —SO₂R¹⁵, (iv) —OCF₃ or

(v) C1-8 alkyl substituted with 1-5 of group selected from (a) halogen,(b) —NR¹¹R¹², (c) —OR¹³, (d) a C5-10 mono- or bi-cyclic carboring, (e)nitro, (f) CF₃, (g) cyano, (h) a 5-10 membered mono- or bi-cyclicheteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵ and (m) OCF₃, wherein atleast one group is selected from a C5-10 mono- or bi-cyclic carboring ora 5-10 membered mono- or bi-cyclic heteroring, —SO₂R¹⁵ or OCF₃,

above CycA is C5-10 mono- or bi-cyclic carboaryl or partially orcompletely saturated one, or 5-10 membered mono- or bi-cyclic heteroarylcontaining 1-2 of nitrogen, 1-2 of oxygen and/or 1 of sulfur, orpartially or completely saturated one thereof.

Particularly preferably, [I] (1) C1-4 alkyl, (2) C2-4 alkenyl, (3) C2-4alkynyl, (4) CycA or (5) C1-4 alkyl, C2-4 alkenyl or C2-4 alkynylsubstituted with CycA which is preferably cyclopentane, cyclohexane,benzene, naphthalene, pyrrolidine, piperidine, piperazine, morpholine,pyrrole, furan, thiophene, pyridine, pyrimidine, pyrazine, pyridazine,indole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline,phthalazine, benzothiophene, benzofuran, benzoxazole,tetrahydroquinoline, tetrahydroquinazoline, tetrahydroquinoxaline,optionally substituted with 1-5 of R^(27a) or

[II] (a) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with agroup selected from halogen, CF₃, nitro, cyano or NR¹⁸R¹⁹ or

(b) (1) CycA which contains 1-5 of substituent R²⁷, or

(2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with CycA whichcontains 1-5 of substituent R²⁷,

wherein at least one of R²⁷ described in (1) and (2) is selected from

(i) a C5-10 mono- or bi-cyclic carboring,

(ii) a 5-10 membered mono- or bi-cyclic heteroring,

(iii) —SO₂R⁵, (iv) —OCF₃, or

(v) C1-8 alkyl substituted with 1-5 of group selected from (a) halogenatom, (b) —NR¹¹R¹², (c) —OR¹³, (d) a C5-10mono- or bi-cyclic carboring,(e) nitro, (f) CF₃, (g) cyano, (h) a 5-10 membered mono- or bi-cyclicheteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵ or (m) —OCF₃, wherein atleast one group is selected from a C5-10 mono- or bi-cyclic carboring, a5-10 membered mono- or bi-cyclic heteroring, —SO₂R¹⁵ or —OCF₃, and

CycA is preferably cyclopentane, cyclohexane, benzene, naphthalene,pyrrolidine, piperidine, piperazine, morpholine, pyrrole, furan,thiophene, pyridine, pyrimidine, pyrazine, pyridazine, indole,isoindole, quinoline, isoquinoline, quinazoline, quinoxaline,phthalazine, benzothiophene, benzofuran, benzoxadiazole,tetrahydroquinoline, tetrahydroquinazoline, or tetrahydroquinoxaline.

In the formula (I), AA¹ is preferably a single bond,

which is formed with R, but more preferably, AA¹ is a single bond or

Any group represented by R¹ is preferable, but more preferably, R¹ ishydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with NH₂, C1-4alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole. Particularly preferably, R¹ is hydrogen, C1-8alkyl, phenyl or C1-8 alkyl substituted with C1-4 alkoxy or phenyl.Then, any group represented by R² is preferable, but hydrogen isparticularly preferable.

And C3-6 alkylene which R¹ and R² together form is also preferable.

Any group represented by R³ is preferable, but more preferably R³ ishydrogen or C1-4 alkyl.

And C2-4 alkylene which R³ and R¹ together form is also preferable.

In the formula (I), any group represented by AA² is all preferable, butmore preferably, AA² is a single bond,

Particularly preferably, AA² is a single bond,

Any group represented by R⁴ is preferable, but more preferably, R⁴ ishydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with NH₂, C1-4alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole. Particularly preferably, R⁴ is hydrogen, C1-8alkyl, phenyl or C1-8 alkyl substituted with C1-4 alkoxy or phenyl.Then, any group represented by R⁵ is preferable, and hydrogen isparticularly preferable.

And C3-6 alkylene which R⁴ and R⁵ together form is also preferable.

Any group represented by R⁶ is preferable, but more preferably R⁶ ishydrogen or C1-4 alkyl.

And C2-4 alkylene which R⁶ and R⁴ together form is also preferable.

Any group represented by R⁴⁸ is preferable, but more preferably, R⁴⁸ is

[I] hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,or

[II] C2-6 alkylene, wherein one carbon atom may be replaced by oxygen,sulfur or —NR⁴⁷—, wherein R⁴⁷ is hydrogen or C1-4 alkyl to be formedtogether with R⁴, when AA¹ is a single bond. Particularly preferably,R⁴⁸ is [I] hydrogen atom or C1-4 alkyl, or

[II] when AA¹ is a single bond, taken together with R to formtetramethylene, pentamethylene, —CH₂—CH₂—O—CH₂—CH₂—,—CH₂—CH₂—NH—CH₂—CH₂— or —CH₂—CH₂—N(CH₃)—CH₂—CH₂—.

In the formula (I), any group which AA¹ and AA² together form ispreferable, but preferably, it is

particularly preferably, it is

Any group represented by R⁷ is preferable. More preferably, R⁷ ishydrogen atom, C1-8 alkyl, phenyl, or C1-8 alkyl substituted with NH₂,C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole.

Particularly preferably, R⁷ is hydrogen, C1-8 alkyl, phenyl, or C1-8alkyl substituted with C1-4 alkoxy or phenyl. Then, any grouprepresented by R⁸ is preferable, but hydrogen is most preferable.

And C3-6 alkylene which R⁷ and R⁸ together form is also preferable.

Any group represented by R⁹ is preferable, but more preferably R⁹ ishydrogen or C1-4 alkyl.

And C2-4 alkylene which R⁹ and R⁷ together form is also preferable.

Any group represented by R¹⁰ is preferable, but more preferably R¹⁰ isC1-6 alkyl, C2-4 alkenyl, CycA or C1-6 alkyl or C2-4 alkenyl substitutedwith COR⁷¹, NR⁷²R⁷³, hydroxy, OR⁷⁴ or CycA, particularly preferably C1-4alkyl, or C1-4 alkyl substituted with phenyl, NR⁷²R⁷³ or C3-6cycloalkyl.

Any group represented by R¹⁰ is preferable, but more preferably R¹⁰ isC1-6 alkyl, CycA or C1-6 alkyl substituted with COR⁷¹, NR⁷²R⁷³, hydroxy,OR⁷⁴ or CycA, more preferably C1-4 alkyl, C2-4 alkenyl, or C1-4 alkyl orC2-4 alkenyl substituted with phenyl, NR⁷²R⁷³, C3-6 cycloalkyl,piperidine or pyrrolidine.

is preferably,

and more preferably,

In the ring represented by

the C5-8 carbocycle which is a condensed ring of the rings representedby

or 5-8 membered heteroring which contains 1 or 2 of nitrogen, 1 ofoxygen and/or 1 of sulfur atom, are all preferable, but more preferably,C5-6 carboring or 5-6 membered heteroring containing 1 or 2 of nitrogen,1 of oxygen and/or 1 of sulfur atom, concretely, cyclopentane,cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene,benzene, pyridine, piperidine, pyrrole, pyrrolidine, furan, dioxane,dioxole, pyran, thiophene, thian, thiepine, oxathiolane, oxazolidine,pyrazole, oxazole, pyrazine, pyrimidine, pyridazine.

R⁸³ is preferably hydrogen atom, C1-4 alkyl, or C1-4 alkyl substitutedwith Cyc, cyano, —OR⁶⁹ or —COR⁶⁸, and more preferably C1-4 alkyl or C1-4alkyl substituted with Cyc.

R¹⁰ is preferably —OR⁷⁴, more preferably hydroxy, C1-4 alkoxy, or C1-4alkoxy substituted with phenyl.

In the compounds of formula (I), the following compounds are preferred;

the compound of (I-1A)

wherein all symbols have the same meanings as above, the compound offormula (I-2A)

wherein all symbols have the same meanings as above, the compound offormula (I-3A)

wherein all symbols have the same meanings as above, the compound offormula (I-4A)

wherein all symbols have the same meanings as above, the compound offormula (I-5A)

wherein all symbols have the same meanings as above, the compound offormula (I-6A)

wherein all symbols have the same meanings as above, the compound offormula (I-7A)

wherein all symbols have the same meanings as above, the compound offormula (I-8A)

wherein all symbols have the same meanings as above, the compound offormula (I-9A)

wherein all symbols have the same meanings as above, the compound offormula (I-10A)

wherein all symbols have the same meanings as above, the compound offormula (I-1B)

wherein all symbols have the same meanings as above, the compound offormula (I-2B)

wherein all symbols have the same meanings as above, the of formula(I-3B)

wherein all symbols have the same meanings as above, the compound offormula (I-1C)

wherein all symbols have the same meanings as above, the compound offormula (I-2C)

wherein all symbols have the same meanings as above, the compound offormula (I-3C)

wherein all symbols have the same meanings as above, the compound offormula (I-4C)

wherein all symbols have the same meanings as above, the compound offormula (I-5C)

wherein all symbols have the same meanings as above, the compound offormula (I-6C)

wherein all symbols have the same meanings as above, the compound offormula (I-7C)

wherein all symbols have the same meanings as above, the compound offormula (I-8C)

wherein all symbols have the same meanings as above, the compound offormula (I-9C)

wherein all symbols have the same meanings as above, the compound offormula (I-10C)

wherein all symbols have the same meanings as above, the compound offormula (I-1D)

wherein all symbols have the same meanings as above, and the compound offormula (I-2D)

wherein all symbols have the same meanings as above.

Particularly, the compounds described in the following tables 1 to 30and the compounds described in the examples or non-toxic salts thereofare preferable. In the following tables, all symbols have the samemeanings as above.

TABLE 1 (I-1A-1)

No. R²⁷ 1 3-F 2 2-CN 3 3-CN 4 3-NO₂ 5 4-NO₂ 6 3-CH₃ 7 2-CH₂—Cl 84-CH₂—Cl 9 4-CH₂CH₃ 10 4-(CH₂)₃CH₃ 11 4-N(CH₃)₂ 12 4-OCH₂CH₃ 132,3-di-CH₃ 14 3,5-di-F 15 3,4-di-F 16 2-OCF₃ 17 3-OCF₃ 18 4-CONH₂ 193-CONH₂ 20 4-COOH 21 4-OCH₂COOH 22 4-O(CH₂)₅CH₃ 23 4-CH₂CH(CH₃)₂ 243-COOH 25 3-OCH₂COOH 26 3-O(CH₂)₅CH₃ 27 3-CH₂CH(CH₃)₂ 28 2-OCH₂COOH 292-O(CH₂)₅CH₃ 30 2-CH₂CH(CH₃)₂

TABLE 2 (I-2A-1)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

TABLE 3 (I-3A-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 4 (I-4A-1)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 5 (I-5A-1)

No. R⁷⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 6 (I-6A-1)

No. R⁷⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 7 (I-1B-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 8 (I-2B-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 9 (I-1C-1)

No. R²⁷ 1 3-F 2 2-CN 3 3-CN 4 3-NO₂ 5 4-NO₂ 6 3-CH₃ 7 2-CH₂—Cl 84-CH₂—Cl 9 4-CH₂CH₃ 10 4-(CH₂)₃CH₃ 11 4-N(CH₃)₂ 12 4-OCH₂CH₃ 132,3-di-CH₃ 14 3,5-di-F 15 3,4-di-F 16 2-OCF₃ 17 3-OCF₃ 18 4-CONH₂ 193-CONH₂ 20 4-COOH 21 4-OCH₂COOH 22 4-O(CH₂)₅CH₃ 23 4-CH₂CH(CH₃)₂ 243-COOH 25 3-OCH₂COOH 26 3-O(CH₂)₅CH₃ 27 3-CH₂CH(CH₃)₂ 28 2-OCH₂COOH 292-O(CH₂)₅CH₃ 30 2-CH₂CH(CH₃)₂

TABLE 10 (I-2C-1)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

TABLE 11 (I-3C-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 12 (I-4C-1)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 13 (I-5C-1)

No. R⁷⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 14 (I-6C-1)

No. R⁷⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 15 (I-1D-1)

No. R⁸³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 16 (I-2D-1)

No. R⁸³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 17 (I-7A-1)

No. R²⁷ 1 3-F 2 2-CN 3 3-CN 4 3-NO₂ 5 4-NO₂ 6 3-CH₃ 7 2-CH₂—Cl 84-CH₂—Cl 9 4-CH₂CH₃ 10 4-(CH₂)₃CH₃ 11 4-N(CH₃)₂ 12 4-OCH₂CH₃ 132,3-di-CH₃ 14 3,5-di-F 15 3,4-di-F 16 2-OCF₃ 17 3-OCF₃ 18 4-CONH₂ 193-CONH₂ 20 4-COOH 21 4-OCH₂COOH 22 4-O(CH₂)₅CH₃ 23 4-CH₂CH(CH₃)₂ 243-COOH 25 3-OCH₂COOH 26 3-O(CH₂)₅CH₃ 27 3-CH₂CH(CH₃)₂ 28 2-OCH₂COOH 292-O(CH₂)₅CH₃ 30 2-CH₂CH(CH₃)₂

TABLE 18 (I-8A-1)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

TABLE 19 (I-9A-1)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 20 (I-10A-1)

No. R⁷⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 21 (I-3B-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

TABLE 22 (I-7C-1)

No. R²⁷ 1 3-F 2 2-CN 3 3-CN 4 3-NO₂ 5 4-NO₂ 6 3-CH₃ 7 2-CH₂—Cl 84-CH₂—Cl 9 4-CH₂CH₃ 10 4-(CH₂)₃CH₃ 11 4-N(CH₃)₂ 12 4-OCH₂CH₃ 132,3-di-CH₃ 14 3,5-di-F 15 3,4-di-F 16 2-OCF₃ 17 3-OCF₃ 18 4-CONH₂ 193-CONH₂ 20 4-COOH 21 4-OCH₂COOH 22 4-O(CH₂)₅CH₃ 23 4-CH₂CH(CH₃)₂ 243-COOH 25 3-OCH₂COOH 26 3-O(CH₂)₅CH₃ 27 3-CH₂CH(CH₃)₂ 28 2-OCH₂COOH 292-O(CH₂)₅CH₃ 30 2-CH₂CH(CH₃)₂

TABLE 23 (I-8C-1)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

TABLE 24 (I-9C-1)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 25 (I-10C-1)

No. R⁷⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 26 (I-3D-1)

No. R⁸³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 27 (I-7A-2)

No. R²⁷ 1 2-CH₂N(CH₃)₂ 2 3-CH₂N(CH₃)₂ 3 4-CH₂N(CH₃)₂ 4

5

6

7

8

9

TABLE 28 (I-7C-2)

No. R²⁷ 1 2-CH₂N(CH₃)₂ 2 3-CH₂N(CH₃)₂ 3 4-CH₂N(CH₃)₂ 4

5

6

7

8

9

TABLE 30 (I-11C-1)

No. R—AA1—AA2 1

2

3

4

5

6

The Methods for the Preparation of the Compound of the Present Invention

(1) Among the compounds of formula (I), the compound wherein AA¹ and AA²represent a single bond at the same time, none of R, R⁷, R⁸, R¹⁰or

contains carboxy, hydroxy, amino, thiol, guanidino, amidino orphosphono, and R does not represent hydrogen, i.e. the compound offormula (IA)

wherein R^(A), R^(7A), R^(8A) and R^(10A) and

have the same meanings as R, R⁷, R⁸, R¹⁰ and

respectively, with proviso that none of them contains carboxy, hydroxy,amino, thiol, guanidino, amidino or phosphono and R^(A) does notrepresent hydrogen, may be prepared by subjecting to a reaction acompound of formula (IIA)

wherein X is halogen atom or a leaving group such as mesyl and tosyl andthe other symbols have the same meanings as above, and a compound offormula (IIB)

wherein all symbols have the same meanings as above. The reaction of thecompound of formula (IIA) and the compound of formula (IIB) is, forexample, carried out in an organic solvent (dimethylformamide,acetonitrile, etc.) in the presence or absence of a tertiary amine(triethylamine, N-methylmorpholine, diisopropylethylamine, etc.), a base(sodium hydride etc.), an alkali (potassium carbonate, sodium carbonate,etc.) or fluoride (sodium fluoride, potassium fluoride, cesium fluoride,etc.) at a temperature of 20 to 40° C.

[2] Among the compounds of formula (I), wherein AA¹ and AA² are a singlebond at the same time, R is hydrogen and none of R⁷, R⁸, R¹⁰ and

contains carboxy, hydroxy, amino, thiol, guanidino, amidino, phosphono,i.e. the compound of formula (IB)

wherein all symbols have the same meanings as above, may be prepared bysubjecting to a deprotection reaction the compound, among the compoundsof formula (IA), wherein R^(A) is a protective group of amino, i.e. thecompound of formula (IA-1)

wherein R^(A-1) is a protective group of amino and the other symbolshave the same meanings as above.

As protective groups for amino group, for example, benzyloxycarbonyl,t-butoxycarbonyl, trifluoroacetyl, 9-fluorenylmethoxycarbonyl may beincluded, but other groups that can be easily and selectively eliminatedmay also be used instead. For example, the groups described in T. W.Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991may be used.

Deprotection reaction for protective groups of amino group is known, forexample,

1) deprotection reaction under alkaline conditions,

2) deprotection reaction under acidic conditions,

3) deprotection reaction by hydration, etc. may be included.

To explain these methods concretely,

1) deprotection reaction under alkaline conditions is carried out, forexample, in an organic solvent (methanol, tetrahydrofuran, dioxane,dimethylformamide, etc.) using a hydroxide of alkali metals (sodiumhydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide ofalkaline earth metals (barium hydroxide, calcium hydroxide, etc.),organic amine (triethylamine, N-methylmorpholine, diisopropylethylamine,piperidine, etc.) or a quaternary ammonium salt (tetrabutyl ammoniumfluoride etc.) or a solution thereof or a mixture thereof at atemperature of 0 to 40° C.;

2) deprotection reaction under acidic conditions is carried out, forexample, in an organic solvent (methylene chloride, chloroform, dioxane,ethyl acetate, anisole, etc.), using organic acid (acetic acid,trifluoroacetic acid, methanesulfonic acid, etc.) or inorganic acid(hydrochloric acid, sulfuric acid, etc.) or a mixture thereof(hydrobromic acid/acetic acid, etc.) at a temperature of 0 to 100° C.;

3) deprotection reaction by hydration is, for example, carried out in asolvent (ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethylether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene,toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitrilessuch as acetonitrile, amides such as dimethylformamide, water, ethylacetate, acetic acid or a mixture of more than two from above, etc.) inthe presence of a catalyst (palladium-carbon, palladium black, palladiumhydroxide, platinum oxide, Raney nickel, etc.) under the atmosphere ofhydrogen of normal or suppressed pressure, or in the presence ofammonium formate at a temperature of 0 to 200° C.

As easily understood by those skilled in the art, the compounds of thepresent invention may be easily prepared by selecting these reactions.

[3] Among the compounds of formula (I), wherein AA¹ and AA² are a singlebond at the same time, and at least one of R, R⁷, R⁸, R¹⁰ or

contains carboxy, hydroxy, amino, thiol, guanidino, amidino, phosphonoor R is hydrogen, i.e. the compound of formula (IC)

wherein R^(C), R^(7C), R^(8C), R^(10C) and

have the same meanings as R, R⁷, R⁸, R¹⁰ and

respectively, with proviso that at least one contains carboxy, hydroxy,amino, thiol, guanidino, amidino, phosphono or R is hydrogen, may beprepared by subjecting to deprotection reaction of protective groups ofcarboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, thecompound among the compounds of formula (IA) prepared by a previousmethod, wherein at least one of R^(A), R^(7A), R^(8A), R^(10A) or

contains a protected form of carboxy, hydroxy, amino, thiol, guanidino,amidino or phosphono, i.e. the compound of formula (IA-2)

wherein R^(A-2), R^(7A-2), R^(8A-2), R^(10A-2)

have the same meanings as R^(A), R^(7A), R^(8A), R^(10A) and

respectively, with proviso that at least one of R^(A-2), R^(7A-2),R^(8A-2), R^(10A-2) and

is a protected form of carboxy, hydroxy, amidno, thiol, guanidino,amidino or phosphono, or R^(A-2) is a protective group of amino, and theother symbols have the same meanings as above, or the compound among thecompounds of formula (IB) prepared by a method above described, whereinat least one group is a protected form of carboxy, hydroxy, amino,thiol, guanidino, amidino or phosphono, i.e. the compound of formula(IB-1)

wherein all symbols have the same meanings as above.

Protective groups for carboxy include, for example, methyl, ethyl,t-butyl and benzyl.

Protective groups for hydroxy include, for example, methoxymethyl,2-tetrahydropyranyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyland benzyl.

Protective groups for amino include the ones shown above.

Protective groups for thiol include, for example, benzyl, methoxybenzyl,methoxymethyl, 2-tetrahydropyranyl, diphenylmethyl and acetyl.

Protective groups for guanidino and amidino include, for example,benzyloxycarbonyl, t-butoxycarbonyl and 9-fluorenylmethoxycarbonyl.

Protective groups for phosphono include, for example, C1-2 alkyl,phenyl, benzyl, 2,2,2-trichloroethyl and cyanoethyl.

As to protective groups for carboxy, hydroxy, amino, thiol, guanidino,amidino or phosphono group, other groups than above listed may also beused instead, if easily and selectively eliminated. For example, thegroups described in T. W. Greene, Protective Groups in OrganicSynthesis, Wiley, New York, 1991 may be used.

Deprotection reactions of the protective groups of carboxy, hydroxy,amino, thiol, guanidino or amidino are well known, for example,

1) a deprotection reaction under alkaline conditions,

2) a deprotection reaction under acidic conditions,

3) a deprotection reaction by hydration,

4) a deprotection reaction of silyl-containing groups, etc. may beincluded.

The methods of 1), 2) and 3) are carried out by the methods describedabove.

4) A deprotection reaction of silyl-containing group is carried out, forexample, in a water-miscible organic solvent (tetrahydrofuran,acetonitrile, etc.) using tetrabutylammonium fluoride at a temperatureof 0 to 40° C.

Deprotection reaction of protective groups of phosphono is known, forexample,

(a) Elimination of C1-2 alkyl is carried out in an organic solvent suchas chloroform using halogenated trimethylsilyl (chlorotrimethylsilyl,bromotrimethylsilyl, iodotrimethylsilyl, etc.) as a reagent, in thepresence or absence of alkali metal iodide (sodium iodide, potassiumiodide, etc.) at a temperature of 0 to 40° C.

(b) Elimination of phenyl is carried out under atmosphere of hydrogen inan organic solvent (methanol, ethanol, tetrahydrofuran, etc.) or withouta solvent in the presence or absence of a catalyst such as platinumoxide and an organic acid such as acetic acid or an inorganic acid suchas hydrochloric acid at a temperature of 0 to 50° C. for 24 hours to 3days.

(c) Elimination of benzyl is carried out under atmosphere of hydrogen inan organic solvent (methanol, ethanol, tetrahydrofuran, pyridine, aceticacid, etc.) in the presence of a catalyst (palladium-carbon, palladiumblack, palladium hydroxide, etc.) at a temperature of 0 to 50° C.

(d) Elimination of 2,2,2-trichloroethyl is carried out in an organicsolvent (methanol, ethanol, tetrahydrofuran, etc.) or without a solventusing a micropowder of zinc and others and an organic acid such asacetic acid or an inorganic acid such as hydrochloric acid at atemperature of 0 to 50° C.

(e) Elimination of cyanoethyl is carried out in a solvent (water,methanol, ethanol, tetrahydrofuran, pyridine, etc.) or without asolvent, in the presence of a base (triethylamine, dimethylamine,t-butylamine, etc.) at a temperature of 0 to 100° C.

As easily understood by those skilled in the art, the target compoundsof the present invention may be easily prepared by selecting thesereactions.

[4] Among the compounds of formula (I), wherein AA¹ and AA² do notrepresent a single bond at the same time, and none of R, AA¹, AA², R⁷R⁸, R¹⁰ and

 contains carboxy, hydroxy, amino, thiol, guanidino, amidino, phosphono,i.e. the compound of formula (ID)

 wherein AA^(1A) and AA^(2A) have the same meanings as AA¹ and AA², withproviso that no group contains carboxy, hydroxy, amino, thiol,guanidino, amidino, phosphono, and AA^(1A) and AA^(2A) do not representa single bond at the same time, and the other symbols have the samemeanings as above, may be prepared according to the following method of(A) or (B).

(A) The compound of formula (ID) may be prepared by subjecting toamidation reaction the compound of formula (IIC)

R^(A)-AA^(1A)-AA^(2A)—OH  (IIC),

wherein all symbols have the same meanings as above, and the compound offormula (IB) above described.

Amidation reaction is known, for example,

1) a method using acid halide,

2) a method using mixed anhydride,

3) a method using a condensing agent (EDC, DCC, etc.), etc.

To explain these methods concretely,

1) the method using acid halide is carried out, for example, bysubjecting to a reaction carboxylic acid and acid-halogenating agent(oxalyl chloride, thionyl chloride, etc.) in an organic solvent(chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.)or without a solvent, at a temperature between −20° C. and refluxingtemperature, and then subjecting to a reaction thus obtained acid halidein the presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.) in an inert organicsolvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran,etc.) at a temperature between 0 to 40° C.

And it may be carried out by subjecting to a reaction with acid halidein an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueousalkali solution (an aqueous solution of sodium bicarbonate or sodiumhydroxide, etc.) at a temperature between 0 to 40° C.

2) The method using mixed anhydride is carried out, for example, bysubjecting to a reaction in an organic solvent (chloroform, methylenechloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent, inthe presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.), carboxylic acid with acidhalide (pivaloyl chloride, tosyl chloride, mesylchloride, etc.) or acidderivative (chloroethyl formate, chloroisobutyl formate, etc.) at atemperature between 0 to 40° C., and then subjecting to a reaction thusobtained mixed anhydride with amine in an organic solvent (chloroform,methylene chloride, diethyl ether, tetrahydrofuran, etc.) at atemperature between 0 to 40° C.

3) The method using a condensing agent is carried out, for example, inan organic solvent (chloroform, methylene chloride, dimethylformamide,diethyl ether, tetrahydrofuran, etc.) or without a solvent, in thepresence or absence of a tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.), using a condensing agent(1,3-dicychlorohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,etc.) in the presence or absence of 1-hydroxybenzotriazole (1-HOBt), bysubjecting to a reaction carboxylic acid and amine at a temperaturebetween 0 and 40° C.

The reactions 1), 2) and 3) are desirably carried out under atmosphereof inert gas (argon, nitrogen, etc.) and anhydrous conditions.

(B) The compound of formula (ID) may be prepared by subjecting to areaction the compound of formula (IID)

 wherein all symbols have the same meanings as above, and the compoundof formula (IIB) above described. The reaction of the compound offormula (IID) and the compound of formula (IIB) is carried out accordingto the same method of the reaction of the compound of formula (IIA) andthe compound of formula (IIB) above described.

[5] Among the compounds of formula (I), wherein AA¹ and AA² do notrepresent a single bond at the same time, and at least one of R, AA¹,AA², R⁷, R⁸, R¹⁰ and

represents a group which contains carboxy, hydroxy, amino, thiol,guanidino, amidino or phosphono, i.e. the compound of formula (IE)

wherein R^(E), AA^(1E), AA^(2E), R^(7E), R^(8E), R^(10E) and

have the same meanings as R, AA¹, AA², R⁷, R⁸, R¹⁰ and

respectively, with proviso that at least one of them contains carboxy,hydroxy, amino, thiol, guanidino, amidino or phosphono, or R^(E) ishydrogen, and the other symbols have the same meanings as above, may beprepared by subjecting to a deprotection reaction of protective group ofcarboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, thecompound among the compounds of formula (ID), which contains at leastone protected form of carboxy, hydroxy, amino, thiol, guanidino, amidinoor phosphono, i.e. the compound of formula (ID-1)

wherein R^(A-3), AA^(1A-3), AA^(2A-3), R^(7A-3), R^(8A-3), R^(10A-3) and

have the same meanings as R^(A), AA^(1A), AA^(2A), R^(7A), R^(8A),R^(10A) and

respectively, with proviso that at least one of R^(A-3), AA^(1A-3),AA^(2A-3), R^(7A-3), R^(8A-3), R¹⁰⁻³ and

contains at least one protected form of carboxy, hydroxy, amino, thiol,guanidino, amidino or phosphono or R^(A-3) is a protected form of amino,and the other symbols have the same meanings as above.

Deprotection reaction of the protective groups of carboxy, hydroxy,amino, thiol, guanidino, amidino or phosphono is carried out accordingto the method described above.

The compound of formula (IA) above described may also be prepared bysubjecting the compound of formula (IB) to a reaction of (A) amidation,(B) sulfonamideation, (C) forming an urea, (D) forming an urethane, (E)N-alkylation.

(A) Amidation Reaction is Carried out by Subjecting to a Reaction theCompound of Formula (IB) and the Compound of Formula (IIE-A)

wherein R^(16A) has the same meaning as R¹⁶, but R^(16A) represents agroup which does not contain carboxy, hydroxy, amino, thiol, guanidinoor amidino. Amidation reaction is carried out according to the methoddescribed above.

(B) Sulfonamidation Reaction is Carried out by Subjecting to a Reactionthe Compound of Formula (IB) and the Compound of Formula (IIE-B)

wherein X^(B) is halogen and the other symbols are the same meanings asabove.

Sulfonamidation reaction is known, for example, it is carried out bysubjecting sulfonic acid to a reaction with acid halide (oxalylchloride, thionyl chloride, etc.) at a temperature of −20° C. torefluxing temperature in an inert organic solvent (chloroform, methylenechloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent,followed by subjecting thus obtained sulfonyl halide to a reaction withamine in the presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.) in an inert organicsolvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran,etc.) at a temperature of 0 to 40° C.

(C) A Reaction to Form Urea is Carried out According to the FollowingMethod of (1) or (2).

(1) A Method of Subjecting to a Reaction the Compound of Formula (IB)and the compound of formula (IIE-C-1)

R^(16A)—N═C═O  (IIE-C-1)

The reaction is carried out, for example, in an organic solvent(tetrahydrofuran, methylene chloride, diethyl ether, etc.) at atemperature of 0 to 100° C.

(2) A Method of Subjecting to a Reaction the Compound of Formula (IB)and the Compound of Formula (IIE-C-2)

 in the presence of phosgene or 1,1-carbonyldiimidazole

This reaction is carried out, for example, in an organic solvent(tetrahydrofuran, methylene chloride, diethyl ether, dimethylformamide,etc.) at a temperature of 0 to 120° C.

(D) A Reaction to Form Urethane is Carried out According to theFollowing Method of (1) or (2).

(1) A Method of Subjecting to a Reaction the Compound of Formula (IB)and the Compound of Formula (IIE-D-1)

wherein all symbols have the same meanings as above.

This reaction is carried out, for example, in an organic solvent(tetrahydrofuran, methylene chloride, diethyl ether, etc.) at atemperature of −78 to 40° C.

(2) A Method of Subjecting to a Reaction the Compound of Formula (IB)and the Compound of Formula (IIE-D-2)

R^(16A)—OH  (IIE-D-2)

in the presence of N,N′-disuccinylcarbonate (DSC)

This reaction is carried out, for example, in an organic solvent(tetrahydrofuran, methylene chloride, diethyl ether, dimethylformamide,etc.) at a temperature of −78 to 120° C.

(E) N-Alkylation Reaction is Carried out by Subjecting to a Reaction theCompound of Formula (IB) and the Compound of (IIE-E)

R^(X)—X^(B)  (IIE-E),

wherein R^(X) is C1-8 alkyl, Cyc, C1-8 alkyl substituted with Cyc ornitro, or

N-alkylation is known, for example, it is carried out in an inertorganic solvent (dimethylformamide, dimethylsulfoxide, chloroform,methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, etc.)in the presence or absence of a base (triethylamine, pyridine, etc.) ata temperature of 0 to 100° C.

Furthermore, the compound of formula (ID) may also be prepared accordingto the method of 1) or 2).

1) The compound of formula (ID) may be prepared by subjecting toamidation reaction the compound among the compounds of formula (IE),wherein R^(E) is hydrogen atom, AA^(1A) is a single bond, and none ofAA^(2E), R^(7E), R^(8E),

 or R^(10E) contains carboxy, hydroxy, amino, thiol, guanidino, amidinoor phosphono, i.e. the compound of formula (IE-1)

 and the compound of formula (IIF)

R^(A)-AA^(1A)-OH  (IIF),

 wherein all symbols have the same meanings as above.

2) The compound of formula (ID) may also be prepared by the reactions ofthe compound among the compounds of formula (IE), wherein R^(E) ishydrogen, and none of AA^(1E), AA^(2E), R^(7E), R^(8E),

 and R^(10E) contains carboxy, hydroxy, amino, thiol, guanidino, amidinoor phosphono, i.e. the compound of formula (IE-2)

 wherein all symbols have the same meanings as above, and the compoundof formula (IIE-A), (IIE-B), (IIE-C-1), (IIE-C-2), (IIE-D-1), (IIE-D-2)or (IIE-E).

That is, the compound of formula (ID) may also be prepared by subjectingto

2-A) an amidation reaction the compound of formula (IE-2) and thecompound of formula (IIE-A),

2-B) a sulfonamidation reaction the compound of formula (IE-2) and thecompound of formula (IIE-B),

2-C) a reaction to form urea the compound of formula (IE-2) and thecompound of formula (IIE-C-1) or (IIE-C-2),

2-D) a reaction to form urethane the compound of formula (IE-2) and thecompound of formula (IIE-D-1) or (IIE-D-2), or

2-E) an N-alkylation reaction the compound of formula (IE-2) and thecompound of formula (IIE-E).

Amidation, sulfonamidation, reactions to form urea and urethane, andN-alkylation may be carried out according to the methods describedabove.

The compounds of formula (IIA), (IIB), (IIC), (IID), (IIE-A), (IIE-B),(IIE-C), (IIE-D), (IIE-E) and (IIF) are known per se or may be preparedaccording to known methods.

For example, among the compound of formula (IIB), the compound offormula (IIB-1)

is known as CAS No. 4424-20-8 and the compound of formula (IIB-2)

may be prepared according to the following reaction scheme (1).

The compounds of formula (IIA) and (IID) may be prepared according toknown methods, for example, the methods described in J. Med. Chem., 37,563 (1994), EP 0623592-A, etc.

In each reaction of the present specification, reaction products may bepurified by conventional techniques. For example, purification may becarried out by distillation under atmospheric or reduced pressure, byhigh performance liquid chromatography using silica gel or magnesiumsilicate, by washing or by recrystallization, etc. Purification may becarried out after each reaction, or after a series of reactions. Otherstarting materials and agents used in the present invention are knownper se or may be prepared by conventional methods.

Pharmacological Activity of the Compounds of the Present Invention

The compound of formula (I) of the present invention has an inhibitoryactivity against cysteine proteases, and therefore it is useful as anagent for the prophylaxis and/or treatment of inflammatory diseases(periodontitis, arthritis, inflammatory bowel diseases, infectiousdiseases, pancreatitis, hepatitis, glomerulonephritis, endocarditis,myocarditis, etc.), diseases induced by apoptosis (graft versus hostdiseases, rejection of an organ transplantation, acquired immunedeficiency syndrome (AIDS), AIDS-related complex (ARC), adult T cellleukemia, hairy cells leukemia, spondylopathy, disorders of respiratoryapparatus, arthritis, HIV or HTLV-1 related diseases such as uveitis,virus-related diseases such as hepatitis C, cancer, collagenosis(systemic lupus erythematosus, rheumatoid arthritis, etc.), ulcerativecolitis, Sjoegren's syndrome, primary biliary cirrhosis, spontaneousthrombocytopenic purpura, autoimmune hemolytic anemia, myastheniagravis, autoimmune diseases such as insulin dependent (type I) diabetes,diseases accompanying thrombocytopenia (osteomyelodysplasia syndrome,periodic thrombocytopenia, aplastic anemia, spontaneousthrombocytopenia, disseminated intravascular coagulation (DIC), etc.),hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) orhepatitis medicamentosa and cirrhosis, dementia such as Alzheimer'sdiseases and Alzheimer's senile dementia, cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.), diseases induced by disorders of immune response (graft versushost diseases, rejection of an organ transplantation, allergic diseases(bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis,diseases induced by house dusts, irritable pneumonia, food allergy,etc.), psoriasis, rheumatoid arthritis, etc.), auto immune diseases(insulin-dependent (type I) diabetes, systemic lupus erythematosus,Hashimoto's diseases, multiple sclerosis, etc.), desease by decomposingvarious proteins which compose the organism (myodystrophy, cataract,periodontitis, hepatocyte desease by bile acid such as cholestaticcirrhosis, etc.), decomposition of alveolus elastica such as pulmonaryemphysema, ischemic diseases (brain ischemia, brain disorders byischemic reperfusion, myocardial infarction, ischemic hepatopathy,etc.), shock (septic shock, systemic inflammation response syndrome,endotoxin shock, acidosis, etc.), circulatory system disorders(arteriosclerosis, restenosis after percutaneous transluminal coronaryangioplasty (PTCA), etc.)), blood coagulation disorders(thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignanttumor, acquired immune deficiency syndrome (AIDS) and AIDS-relatedcomplex (ARC), parasitic diseases such as malaria, nerve degenerativediseases (Alzheimer-type dementia, Huntington's chorea, Parkinson'sdiseases, multiple sclerosis, traumatic encephalopathy, traumaticspondylopathy, etc.), pulmopathy such as fibroid lungs, bone resorptiondiseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis,hypercalcemia, osteometastasis of cancer etc.), endocrinesthenia such ashyperthyroidism.

It was confirmed by the following experiments that the compounds of thepresent invention of formula (I) have an inhibitory activity againstcysteine protease.

(i) Measurement of Cathepsin K Inhibitory Activity

65 μL of Cathepsin K enzyme reaction buffer (50 mmol/L of2-(N-morpholino)ethanesulfonate, 2 mmol/L of ethylenediaminetetraacetate (EDTA) and 4 mmol/L of dithiothreitol (DTT) were mixed toadjust to pH 5.5), 5 μL of cysteine protease inhibitor solution ofseveral concentrations, 20 μL of synthesized substrate(t-butyloxycarbonyl-L-alanyl-glycyl-L-prolyl-L-arginine-4-methyl-chromanyl-7-amide)solution of several concentrations and 10 μL of cathepsin K enzymesolution were mixed and the increase of fluorescence intensity whenreacted at 37° C. was measured (λ ex (excitation wavelength)=355 nm, λem (fluorescence wavelength)=460 nm). As to the substrate and thecompound of the present invention, enzyme reactions were carried out incombination of several appropriate concentrations and Dixon plotting wasprepared, to define the absolute value of X-coordinate of theintersection point of the graph as Ki value.

It was confirmed that the compound of the present invention of formula(I) had an inhibitory activity more than 50% at 10 μM. For example, theKi values of inhibitory activity of the compounds of example 3, example3 (14) and example 31 were 0.17 μM, 0.10 μM and 0.081 μM respectively.

(ii) Measurement of Cathepsin B Inhibitory Activity

10 μL of Synthesized substrate(carbobenzoxy-L-arginyl-L-arginine-4-methyl-chromanyl-7-amide orcarbobenzoxy-L-phenylalanyl-L-arginine-4-methyl-chromanyl-7-amide)solution of several concentrations, 10 μL of cysteine protease inhibitorsolution of several concentrations, 70 μL of cathepsin B enzyme reactionbuffer (mixture of 400 mmol/L in acetic acid, 4 mmol/L EDTA, 8 mmol/LDDT to adjust to pH 5.5) and 10 μL of cathepsin B enzyme solution weremixed and the increase of fluorescence intensity was measured (λ ex(excitation wavelength)=355 nm, μ em (fluorescence wavelength)=460 nm)when reacted at 37° C.

It was confirmed that the compound of the present invention of formula(I) had an inhibitory activity more than 50% at 10 μM. For example, theinhibitory activity of the compound of example 10 was 95% at 1 μM.

(iii) Measurement of Cathepsin S Inhibitory Activity

10 μL of synthesized substrate(carbobenzoxy-L-leucyl-L-leucyl-L-arguinine-4-methyl-chromanyl-7-amide)solution and 5 μL of cysteine protease inhibitor solution of severalconcentrations, 75 μL of cathepsin S enzyme reaction buffer (100 mmol/Lof sodium phosphate, 2 mmol/L of EDTA, 2 mmol/L of DTT were mixed toadjust to pH 6.5) and 10 μL of cathepsin S enzyme solution were mixedand the increase of fluorescence intensity was measured (λ ex(excitationwavelength)=355 nm, λ em (fluorescence wavelength)=460 nm) when reactedat 37° C.

It was confirmed that the compound of the present invention of formula(I) has an inhibitory effect more than 50% at 10 μM. For example, theinhibitory activity of the compound of example 18 was 98% at 1 μM.

(iv) Measurement of Cathepsin L Inhibitory Activity

5 μL of Synthesized substrate(carbobenzoxy-L-phenylalanyl-L-arguine-4-methyl-chromanyl-7-amide orL-prolyl-L-phenylalanyl-L-arguinine-4-methyl-chromanyl-7-amide) solutionand 5 μL of cysteine protease inhibitor solution of severalconcentrations, 80 μL of cathepsin L enzyme reaction buffer (400 mmol/Lacetic acid, 4 mmol/L EDTA, 8 mmol/L DTT were mixed to adjust to pH 5.5)and 10 μL of cathepsin L enzyme solution were mixed and the increase offluorescence intensity was measured (λ ex (excitation wavelength)=355nm, λ em (fluorescence wavelength)=460 nm) when reacted at 37° C.

It was confirmed that the compound of the present invention of formula(I) had an inhibitory activity of more than 50% at 10 μM. For example,the inhibitory activity of the compound of example 22(4) was 97% at 1μM.

(v) Measurement of Calpain Inhibitory Activity

The activity was measured according to the method described inCalcium-depending protease, Seibutsukagaku-Jikkenhou (BiochemistryExperimental Method) Tanpakubunkaikouso (Protease) I, 57 (1993).

(vi) Measurement of Caspase-1 Inhibitory Activity

50 μL of caspase-1 enzyme reaction solution (20 mmol/L of4-(2-hydroxyethyl)-1-piperazinethanesulfonate-sodium hydroxide buffer pH7.4, 10 mmol/L of potassium chloride, 1.5 mmol/L of magnesium chloride,0.1 mmol/L EDTA, 10% glycerol) and 50 μL of cysteine protease inhibitorsolution of several concentrations, 50 μL of caspase-1 enzyme solutionand 100 μL of synthesized substrate(acetyl-L-tyrosinyl-L-valinyl-L-alanyl-L-asparticacid-4-methyl-chromanyl-7-amide) solution of several concentrations werereacted at 37° C. and the fluorescence intensity was measured (λ ex(excitation wavelength)=355 nm, λ em (fluorescence wavelength)=460 nm).

(vii) Investigation in Bone Resorption Inhibitory Activity Using MouseCalvaria Cultivation System

Mouse neonatal calvaria was cultured in D-minimal essential mediumcontaining cysteine protease inhibitor (mixture of Penicillin Gpotassium (final concentration 100 U/ml), streptomycin sulfate (finalconcentration 0.1 mg/ml), bovine serum albumin (final concentration0.1%), glutamine (final concentration 0.3 mg/ml) in D-minimal essentialmedium) at 37° C. and the calcium concentration in the culture mediumwas measured.

(viii) Bone Resorption Pit Formation Test Using Rabbit Osteoclast Cells

Osteoclast cells collected from rabbit bones were sowed over slices ofbovine cortical bone, ivory or teeth of toothed whale and were culturedat 37° C. in α-minimal essential medium containing final concentration5% of fetal bovine serum and various concentrations of cysteine proteaseinhibitor. The pits formed on the slices by the osteoclast cells wereobserved and at the same time type-I collagen C-terminal telopeptide(CTx) concentration in culture medium was measured.

(ix) Investigation of Immune Reaction Inhibitory Effect UsingAntigen-Sensitized Mouse Spleen Cells

Spleen cells were collected from mice sensitized by ovalbumin (OVA)several times. Inhibitory effect of cysteine protease inhibitors againstimmune response induced by OVA stimulus was investigated, using cytokineconcentration and immunoglobulin concentration in culture solution asindicators.

(x) Investigation in Inhibitory Effect Against Bone Resorption Using theRat PTH Hypercalcemia Model

The effect of cysteine protease inhibitor (compulsory oraladministration, intraperitoneal administration) on bone resorption whichwas promoted by intravenous administration of parathyroid hormone (PTH)solution (30 μg/ml) was investigated in rats, using calciumconcentration in blood as an indicator.

(xi) Studies on Bone Resorption Inhibitory Effect Using TPTx RatPTHrP-Induced Hypercalcemia Model

The effect of cysteine protease inhibitor (compulsory oraladministration, intraperitoneal administration) on bone resorption,promoted by subcutaneous administration of parathyroid hormone relatedpeptide (PTHrP) to a fasting rat (thyroparathyroidectomized; TPTx) wasinvestigated, using calcium concentration in blood as an indicator.

Toxicity

The toxicity of the compounds of the present invention is very low andtherefore it was confirmed that the compounds are safe forpharmaceutical use.

Industrial Applicability

Application to Pharmaceuticals

The compound of formula (I) of the present invention has an inhibitoryactivity against cysteine proteases, and therefore it is useful as anagent for the prophylaxis and/or treatment of inflammatory diseases(periodontitis, arthritis, inflammatory bowel diseases, infectiousdiseases, pancreatitis, hepatitis, glomerulonephritis, endocarditis,myocarditis, etc.), diseases induced by apoptosis (graft versus hostdiseases, rejection of an organ transplantation, acquired immunedeficiency syndrome (AIDS), AIDS-related complex (ARC), adult T cellleukemia, hairy cells leukemia, spondylopathy, disorders of respiratoryapparatus, arthritis, HIV or HTLV-1 related diseases such as uveitis,virus-related diseases such as hepatitis C, cancer, collagenosis(systemic lupus erythematosus, rheumatoid arthritis, etc.), ulcerativecolitis, Sjoegren's syndrome, primary biliary cirrhosis, spontaneousthrombocytopenic purpura, autoimmune hemolytic anemia, myastheniagravis, autoimmune diseases such as insulin dependent (type I) diabetes,diseases accompanying thrombocytopenia (osteomyelodysplasia syndrome,periodic thrombocytopenia, aplastic anemia, spontaneousthrombocytopenia, disseminated intravascular coagulation (DIC), etc.),hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) orhepatitis medicamentosa and cirrhosis, dementia such as Alzheimer'sdiseases and Alzheimer's senile dementia, cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.), diseases induced by disorders of immune response (graft versushost diseases, rejection of an organ transplantation, allergic diseases(bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis,diseases induced by house dusts, irritable pneumonia, food allergy,etc.), psoriasis, rheumatoid arthritis, etc.), autoimmune diseases(insulin-dependent (type I) diabetes, systemic lupus erythematosus,Hashimoto's diseases, multiple sclerosis, etc.), desease by decomposingvarious proteins which compose the organism (myodystrophy, cataract,periodontitis, hepatocyte desease by bile acid such as cholestaticcirrhosis, etc.), decomposition of alveolus elastica such as pulmonaryemphysema, ischemic diseases (brain ischemia, brain disorders byischemic reperfusion, myocardial infarction, ischemic hepatopathy,etc.), shock (septic shock, systemic inflammation response syndrome,endotoxin shock, acidosis, etc.), circulatory system disorders(arteriosclerosis, restenosis after percutaneous transluminal coronaryangioplasty (PTCA), etc.)), blood coagulation disorders(thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignanttumor, acquired immune deficiency syndrome (AIDS) and AIDS-relatedcomplex (ARC), parasitic diseases such as malaria, nerve degenerativediseases (Alzheimer-type dementia, Huntington's chorea, Parkinson'sdiseases, multiple sclerosis, traumatic encephalopathy, traumaticspondylopathy, etc.), pulmopathy such as fibroid lungs, bone resorptiondiseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis,hypercalcemia, osteometastasis of cancer etc.), endocrinesthenia such ashyperthyroidism.

For the purpose described above, the compounds of formula (I), of thepresent invention, non-toxic salts thereof, acid addition salts thereofor hydrates thereof may normally be administered systemically orlocally, usually by oral or parenteral administration.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person at a time are generally from 1 mg to 1000 mg, byoral administration, up to several times per day, and from 1 mg to 100mg, by parenteral administration (preferably intravenousadministration), up to several times per day, or continuousadministration for from 1 to 24 hours per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases wherein doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered in the formof, for example, solid compositions, liquid compositions or othercompositions for oral administration, injections, liniments orsuppositories for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders and granules.

Capsules include hard capsules and soft capsules.

In such solid compositions, one or more of the active compound(s) may beused as a dosage form, as is normal practice, to admix with excipient(e.g. lactose, mannitol, glucose, microcrystalline cellulose, starch),combining agents (hydroxypropyl cellulose, polyvinyl pyrrolidone ormagnesium metasilicate aluminate), disintegrating agents (e.g. cellulosecalcium glycolate), lubricating agents (e.g. magnesium stearate),stabilizing agents, agents to assist dissolution (e.g. glutamic acid orasparatic acid)and the like. The agents may, if desired, be coated withcoating agents (e.g. sugar, gelatin, hydroxypropyl cellulose orhydroxypropylmethyl cellulose phthalate), or be coated with two or morefilms. Further, coating may include containment within capsules ofabsorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceuticallyacceptable solutions, suspensions, emulsions, syrups and elixirs. Insuch compositions, one or more of the active compound(s) are dissolved,suspended or emulsified in diluent commonly used (e.g. purified water,ethanol or mixture thereof). Furthermore, such liquid compositions mayalso comprise wetting agents or suspending agents, emulsifying agents,sweetening agents, flavouring agents, perfuming agents, preservingagents buffer agent etc.

Injections for parenteral administration include solutions, suspensions,emulsions and solids which are dissolved or suspended to use at a timeto use. One or more of the active compound(s) in injections aredissolved, suspended and emulsified in a solvent. The solvents are, forexample, distilled water for injection, physiological salt solution,vegetable oil, propylene glycol, polyethylene glycol, alcohol such asethanol or mixture thereof. Moreover the injections may also includestabilizing agents, agents to assist dissolution (e.g. glutamic acid,aspartic acid or POLYSORBATE80 (registered trade mark)), suspendingagents, emulsifying agents, soothing agents, buffer agents, preservingagents, etc. They are sterilized in the last process or manufactured andprepared by sterile procedure. They may also be manufactured in the formof sterile solid compositions such as freeze-dried one and they may besterilized or dissolved to use in sterile distilled water for injectionor some other solvents immediately before use.

Other compositions for parenteral administration include liquids forexternal use, and ointment, endermic liniments, inhale, spray,suppositories for rectal administration and pessaries for vaginaladministration which comprise one or more of the active compound(s) andare prescribed by methods known per se.

Spray compositions may comprise additional substances other thandiluents: e.g. stabilizing agents (e.g. sodium sulfite hydride),isotonic buffers (e.g. sodium chloride, sodium citrate or citric acid).For preparation of such spray compositions, for example, the methoddescribed in the U.S. Pat. No. 2,868,691 or No. 3,095,355 may be used.

BEST MODE FOR CARRYING OUT THE INVENTION

The following reference examples and examples illustrate the presentinvention, but do not limit the present invention.

The solvents in the parentheses show the eluting or developing solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC.

The solvents in the parentheses in NMR show the solvents used inmeasurement.

REFERENCE EXAMPLE 1

(3S)-1-bromo-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone

Under atmosphere of argon, to a solution of(2S)-2-(t-butoxycarbonylamino)-4-methylpentanoic acid(t-butoxycarbonyl-L-leucine) (37.4 g) in tetrahydrofuran (800 ml) wasadded N-methylmorpholine (33 ml) at −25° C. and the mixture was stirredfor 10 minutes. To the mixture was added chloroethylformate (15.8 ml)and the mixture was stirred for 20 minutes. Thereto was added a solutionof diazomethane in diethyl ether and the mixture was stirred for another2 hours. Thereto was added a mixture of 47% hydrobromic acid-acetic acid(1:1) at 0° C. and the mixture was stirred for 15 minutes. To thereaction mixture was added water and was extracted with a mixture ofethyl acetate-hexane. The organic layer was washed with a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous sodium sulfate andwas concentrated. The residue was washed with cooled hexane to give thetitle compound (27.4 g) having the following physical data.

TLC: Rf 0.56 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 4.89 (m, 1H), 4.53 (m, 1H), 4.08 (m, 2H), 1.80-1.31 (m,12H), 0.97 (m, 6H)

EXAMPLE 1

(3S)-3-(t-butoxycarbonylamino)-5-methyl-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2-hexanone

To a solution of 1,3,4,5-tetrahydro-2H-2-benzazepin(2.2 g) indimethylformamide (30 ml) was added the compound prepared in referenceexample 1 (4.1 g) and the mixture was stirred for 1.5 hours. To thereaction mixture was added diisopropylethylamine (2.3 ml) and themixture was stirred for another 3.5 hours. To the reaction mixture wasadded ice-water and was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous solution of sodium bicarbonate,water and a saturated aqueous solution of sodium chloride successively,dried over anhydrous sodium sulfate and was concentrated. The residuewas purified by column chromatography on silica gel (n-hexane:ethylacetate=5:1-3:1-1:1) to give the compound of the present invention (4.7g) having the following physical data.

TLC: Rf 0.48 (n-hexane:ethyl acetate=6:4);

NMR (CDCl₃): δ 7.20-7.00 (m, 4H), 4.97 (d, J=8.4 Hz, 1H), 4.40-4.30 (m,1H), 3.98 (s, 2H), 3.33 (d, J=18.2 Hz, 1H), 3.30 (d, J=18.2 Hz, 1H),3.17 (t, J=5.3 Hz, 2H), 2.95-2.85 (m, 2H), 1.80-1.70 (m, 2H), 1.42 (s,9H), 1.50-1.20 (m, 3H), 0.892 (d, J=6.6 Hz, 3H), 0.887 (d, J=6.3 Hz,3H).

EXAMPLE 2

(3S)-3-amino-5-methyl-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2-hexanonedihydrochloride

To a solution of the compound prepared in example 1 (187 mg) in methanol(1 ml) was added 4N hydrochloric acid in ethyl acetate (4 ml) at 0° C.and the mixture was stirred for 1 hour. The reaction mixture wasconcentrated to give a crude product of the present invention having thefollowing physical data. The crude product was used in the next reactionwithout further purification.

TLC: Rf 0.71 (chloroform:methanol:28% ammonia water=8:2:0.4);

NMR (CD₃OD): δ 7.50-7.05 (m, 4H), 5.02-4.90 (m, 3H), 4.60-4.30 (m, 2H),3.75-3.60 (m, 2H) 3.20-3.00 (m, 2H); 2.20-2.00 (m, 2H), 1.90-1.60 (m,3H), 1.12-0.90 (m, 6H).

EXAMPLE 3

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzamidecyclohexyl]carboxamide

To a solution of (−)-2-benzamidocyclohexanecarboxylic acid((1R,2S)-2-benzamidocyclohexanecarboxylic acid) (148 mg) and1-hydroxybenzotriazole (107 mg) in dimethylformamide (2 ml) was added1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (134 mg)and the mixture was stirred for 30 minutes, and thereto was added thecompound prepared in example 2 and triethylamine (140 ml) and wasstirred for another 2 hours. To the reaction mixture was added ice-waterand was extracted with ethyl acetate. The organic layer was washed witha saturated aqueous solution of sodium bicarbonate, water and asaturated aqueous solution of sodium chloride successively, dried overanhydrous sodium sulfate and was concentrated. The residue was purifiedby column chromatography on silica gel (chloroform:methanol=1:0-100:1)to give the compound of the present invention as a free compound (225mg). It was converted into its hydrochloride by a known method to givethe hydrochloride having the following physical data.

[Free Compound]

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.85-7.70 (m, 2H), 7.60-6.95 (m, 8H), 6.12 (d, J=8.7 Hz,1H), 4.75-4.60 (m, 1H), 4.35-4.25 (m, 1H), 3.98 and 3.94 (each s,totally 2H), 3.35-3.25 (m, 2H), 3.20-3.05 (m, 2H), 2.95-2.85 (m, 2H),2.80-2.70 (m, 1H), 2.20-1.20 (m, 13H), 0.90-0.65 (m, 6H).

[Hydrochloride]

TLC: Rf 0.64 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.19 and 7.60 (each br, total 1H), 7.86-7.66 (m, 2H),7.53-7.01 (m, 8H), 4.60-4.22 (m, 5H), 3.77-3.45 (m, 3H), 3.04-2.78 (m,3H), 2.19-1.26 (m, 13H), 0.98-0.62 (m, 6H)

EXAMPLE 3(1)-EXAMPLE 3(24)

By the same procedure as described in example 3 using a carboxylic acidcorresponding to (1R,2S)-2-benzamidocyclohexanecarboxylic acid and thecompound prepared in example 2 or a corresponding amine, the compound ofthe present invention having the following physical data was obtained.

EXAMPLE 3(1)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-cyclohexylcarboxamide

TLC: Rf 0.55 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.20-7.00 (m, 4H), 5.90 (d, J=8.0 Hz, 1H), 4.80-4.65 (m,1H), 3.98 (s, 2H), 3.33 (s, 2H), 3.25-3.10 (m, 2H), 2.95-2.80 (m, 2H),2.20-2.00 (m, 1H), 2.00-1.10 (m, 15H), 0.88 (d, J=6.4 Hz, 3H), 0.88 (d,J=6.2 Hz, 3H).

EXAMPLE 3(2)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.90-7.70 (m, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.50-7.35 (m,3H), 7.20-6.95 (m, 4H), 6.08 (d, J=7.8 Hz, 1H), 4.80-4.65 (m, 1H),4.35-4.20 (m, 1H), 3.97 and 3.93 (each s, totally 2H), 3.35-3.20 (m,2H), 3.20-3.05 (m, 2H), 2.95-2.85 (m, 2H), 2.80-2.70 (m, 1H), 2.10-1.20(m, 13H), 0.87, 0.75 and 0.74 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 3(3)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

TLC: Rf 0.57 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.85-7.75 (m, 2H), 7.55-7.40 (m, 3H), 7.20-7.00 (m, 4H),6.72 (d, J=8.1 Hz, 1H), 5.05-4.95 (m, 1H), 3.99 (each s, totally 2H),3.39 (d, J=17.7 Hz, 1H), 3.36 (d, J=17.7 Hz, 1H), 3.25-3.10 (m, 2H),2.95-2.85 (m, 2H), 1.80-1.40 (m, 5H), 0.95 (d, J=6.3 Hz, 3H), 0.92 (d,J=6.3 Hz, 3H).

EXAMPLE 3(4)

4-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

TLC: Rf 0.28 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.75 (d, J=8.8 Hz, 2H), 7.50-7.30 (m, 5H), 7.20-6.90 (m,6H), 6.65 (d, J=8.8 Hz, 1H), 5.12 (s, 2H), 4.96 (dt, J=8.8, 3.8 Hz, 1H),3.99 (s, 2H), 3.40 (d, J=17.6 Hz, 1H), 3.36 (d, J=17.6 Hz, 1H),3.25-3.10 (m, 2H), 2.95-2.85 (m, 2H), 1.90-1.20 (m, 5H), 0.93 (d, J=6.0Hz, 3H), 0.91 (d, J=6.2 Hz, 3H).

EXAMPLE 3(5)

3-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

TLC: Rf 0.36 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.50-7.30 (m, 8H), 7.20-7.00 (m, 5H), 6.70 (d, J=8.4 Hz,1H), 5.11 (s, 2H), 4.96 (dt, J=8.4, 4.0 Hz, 1H), 3.99 (s, 2H), 3.37 (s,2H), 3.25-3.10 (m, 2H), 2.95-2.85 (m, 2H), 1.80-1.20 (m, 5H), 0.94 (d,J=6.4 Hz, 3H), 0.92 (d, J=6.2 Hz, 3H).

EXAMPLE 3(6)

2-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

TLC: Rf 0.31 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.30-8.10 (m, 2H), 7.55-7.35 (m, 6H), 7.20-6.95 (m, 6H),5.18 (d, J=10.6 Hz, 1H), 5.14 (d, J=10.6 Hz, 1H), 4.80-4.70 (m, 1H),3.95 (s, 2H), 3.37 (d, J=17.8 Hz, 1H), 3.31 (d, J=17.8 Hz, 1H),3.20-3.10 (m, 2H), 2.95-2.80 (m, 2H), 1.80-1.00 (m, 5H), 0.75 (d, J=6.0Hz, 3H), 0.66 (d, J=6.2 Hz, 3H).

EXAMPLE 3(7)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]cinnamide

TLC: Rf 0.27 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.62 (d, J=15.6 Hz, 1H), 7.55-7.45 (m, 2H), 7.40-7.30 (m,3H), 7.20-7.00 (m, 4H), 6.41 (d, J=15.6 Hz, 1H), 6.19 (d, J=8.6 Hz, 1H),4.94 (dt, J=8.6, 4.4 Hz, 1H), 3.99 (s, 2H),3.56 (s, 2H), 3.25-3.10 (m,2H), 2.95-2.85 (m, 2H), 1.80-1.20 (m, 5H), 0.93 (d, J=6.0 Hz, 3H), 0.91(d, J=6.2 Hz, 3H).

EXAMPLE 3(8)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-3-cyclopentylpropanamide

TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.20-7.03 (m, 4H), 6.08 (d, J=8.1 Hz, 1H), 4.71 (m, 1H),4.04 (s, 2H), 3.46 (d, J=18.0 Hz, 1H), 3.35 (d, J=18.0 Hz, 1H), 3.23 (m,2H), 2.92 (m, 2H), 2.21 (t, J=7.5 Hz, 2H), 1.80-1.20 and 1.18-1.00(totally 16H), 0.89 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).

EXAMPLE 3(9)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(5-phenylimidazolidin-2,4-dion-3-yl)acetamide

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.50-7.29 (m, 5H), 7.22-6.98 (m, 4H), 6.74-6.51 (m, 1H),6.31, 6.19, 6.14 and 6.11 (each brs, totally 1H), 5.15 (s, 1H),4.78-4.64 (m, 1H), 4.28-4.11 (m, 2H), 3.95and 3.94 (each s, totally 2H),3.43-3.19 (m, 2H), 3.19-3.05 (m, 2H), 2.94-2.83 (m, 2H), 1.80-1.20 (m,5H), 1.00-0.77 (m, 6H).

EXAMPLE 3(10)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(2-phenyl-1,6-dihydropyrimidin-6-on-1-yl)acetamide

TLC: Rf 0.47 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.00 (d, J=6.5 Hz, 1H), 7.65-7.40 (m, 5H), 7.23-7.00 (m,4H), 6.51 (d, J=8.0 Hz, 1H), 6.50 (d, J=6.5 Hz, 1H), 4.74 (ddd, J=12.0,8.0 and 4.2 Hz, 1H), 4.57 (d, J=15.3 Hz, 1H), 4.46 (d, J=15.3 Hz, 1H),3.97 (s, 2H), 3.38 (d, J=17.4 Hz, 1H), 3.28 (d, J=17.4 Hz, 1H),3.22-3.09 (m, 2H), 2.97-2.84 (m, 2H), 1.83-1.20 (m, 5H), 0.87 (d, J=6.3Hz, 6H).

EXAMPLE 3(11)

2-benzoylamino-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

TLC: Rf 0.32 (hexane:ethyl acetate=6:4);

NMR (CDCl₃): δ 12.07 (s, 1H), 8.85 (d, J=8.4 Hz, 1H), 8.02 (dd, J=7.6,2.2 Hz, 2H), 7.65-7.40 (m, 5H), 7.20-7.00 (m, 5H), 6.97 (d, J=8.8 Hz,1H), 5.01 (dt, J=3.6, 8.8 Hz, 1H), 4.00 (s, 2H), 3.42 (d, J=17.4 Hz,1H), 3.36 (d, J=17.4 Hz, 1H), 3.25-3.10 (m, 2H), 3.00-2.85 (m, 2H),2.00-1.60 (m, 5H), 0.95 (d, J=5.8 Hz, 3H), 0.93 (d, J=5.8 Hz, 3H).

EXAMPLE 3(12)

(3S)-5-methyl-3-(2-methylpropoxycarbonylamino)-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)hexan-2-one

TLC: Rf 0.45 (hexane:ethyl acetate=6:4);

NMR (CDCl₃): δ 7.20-7.00 (m, 4H), 5.16 (d, J=8.4 Hz, 1H), 4.55-4.35 (m,1H), 3.97 (s, 2H), 3.83 (d, J=6.6 Hz, 2H), 3.31 (s, 2H), 3.25-3.10 (m,2H), 2.95-2.85 (m, 2H), 2.00-1.20 (m, 6H), 1.00-0.80 (m, 12H).

EXAMPLE 3(13)

(2S)-N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[1-phenethylpiperidin-2-yl]carboxamide

TLC: Rf 0.54 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.35-7.00 (m, 9H), 6.94 and 6.70 (each d, J=8.4 and 7.6Hz, totally 1H), 4.65-4.45 (m, 1H), 3.97 (s, 2H), 3.40-3.10 (m, 5H),3.10-2.65 (m, 6H), 2.60-1.00 (m, 13H), 1.00-0.70 (m, 6H).

EXAMPLE 3(14)

(2S)-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.45 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40-7.00 (m, 9H), 6.35 (d, J=7.5 Hz, 1H), 5.13 (d, J=9.3Hz, 1H), 5.10 (s, 2H), 4.70 (m, 1H), 4.15 (m, 1H), 3.97 (s, 2H), 3.30(s, 2H), 3.16 (m, 2H), 2.90 (m, 2H), 1.80-1.20 (m, 8H), 0.93 (m, 6H),0.86 (m, 6H)

EXAMPLE 3(15)

(2S)-N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.45 (methanol:ethyl acetate=19:1);

NMR (CDCl₃): δ 7.40-7.00 (m, 9H), 6.57 and 6.38 (each brd, J=7.8 Hz,totally 1H), 5.20-5.12 (m, 3H), 4.69 (m, 1H), 4.20 (m, 1H), 3.99 and3.97 (each s, totally 2H), 3.30 (m, 2H), 3.17 (m, 2H), 2.91 (m, 2H),1.80-1.30 (m, 8H), 1.00-0.80 (m, 12H).

EXAMPLE 3(16)

(2S)-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.42 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.49-6.95 (m, 9H), 6.70 and 6.50 (each d, J=7.2 and 6.0Hz, totally 1H), 5.30-4.96 (m, 3H), 4.74-4.58 (m, 1H), 4.30-4.06 (m,1H), 4.01 (s, 2H), 3.50-3.03 (m, 4H), 3.03-2.80 (m, 2H), 2.11-1.20 (m,8H), 1.07-0.74 (m, 12H).

EXAMPLE 3(17)

(2R)-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.42 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.51-6.96 (m, 9H), 6.60 and 6.46 (each d, J=8.4 Hz,totally 1H), 5.30-4.92 (m, 3H), 4.77-4.60 (m, 1H), 4.30-4.06 (m, 1H),3.99 (s, 2H), 3.46-3.04 (m, 4H), 3.04-2.77 (m, 2H), 2.05-1.20 (m, 8H),1.07-0.74 (m, 12H).

EXAMPLE 3(18)

1-cyclohexyl-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]carboxamide

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.24-7.00 (m, 4H), 5.95 (d, J=8.1 Hz, 1H), 4.70 (ddd,J=9.8, 8.1, 3.9 Hz, 1H), 4.01 (s, 2H), 3.40 (d, J=18.0 Hz, 1H), 3.32 (d,J=18.0 Hz, 1H), 3.25-3.14 (m, 2H), 2.97-2.86 (m, 2H)),2.19-2.00 (m, 1H),1.95-1.06 (m, 15H), 0.89 (d, J=6.5 Hz, 3H), 0.88 (d, J=6.5 Hz, 3H).

EXAMPLE 3(19)

N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-3-cyclopentylpropanamide

TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.23-7.00 (m, 4H), 5.95 (d, J=8.4 Hz, 1H), 4.74 (ddd,J=9.8, 8.4, 4.2 Hz, 1H), 4.00 (s, 2H), 3.39 (d, J=18.0 Hz, 1H), 3.31 (d,J=18.0 Hz, 1H), 3.23-3.14 (m, 2H), 2.95-2.86 (m, 2H), 2.29-2.14 (m, 2H),1.96-1.20 and 1.20-0.96 (each m, totally 13H), 0.89 (d, J=6.6 Hz, 3H),0.88 (d, J=6.6 Hz, 3H).

EXAMPLE 3(20)

N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

TLC: Rf 0.52 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.90-7.70 (m, 2H), 7.60-7.33 (m, 4H), 7.22-6.95 (m, 4H),6.24 and 6.17 (each d, J=8.1 Hz, totally 1H), 4.76-4.57 (m, 1H),4.40-4.19 (m, 1H), 3.98 and 3.97 (each s, totally 2H), 3.44-3.22 (m,2H), 3.22-3.02 (m, 2H), 2.96-2.80 (m, 2H), 2.80-2.66 (m, 1H), 2.16-1.15(m, 13H), 0.86, 0.75 and 0.74 (each d, J=6.5 Hz, totally 6H).

EXAMPLE 3(21)

N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide

TLC: Rf 0.52 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.90-7.70 (m, 2H), 7.57-7.31 (m, 4H), 7.21-6.96 (m, 4H),6.34 and 6.20 (each d, J=8.7 Hz, totally 1H), 4.78-4.60 (m, 1H),4.41-4.16 (m, 1H), 4.00 (s, 2H), 3.48-3.24 (m, 2H), 3.24-3.07 (m, 2H),2.98-2.81 (m, 2H), 2.81-2.68 (m, 1H), 2.20-1.20 (m, 13H), 0.87, 0.75 and0.74 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 3(22)

(2S)-N-[1-(2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)acetyl)cyclohexan-1-yl]-4-methyl-2-benzyloxycarbonylamino pentanamide

TLC: Rf 0.39 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.34 (s, 5H), 7.17-7.00 (m, 4H), 6.39 (brs, 1H), 5.12 (d,J=12.3 Hz, 1H), 5.06 (d, J=12.3 Hz, 1H), 5.00 (m, 1H), 4.08 (m, 1H),3.96 (s, 2H), 3.40 (s, 2H), 3.13 (t, J=5.4 Hz, 2H), 2.87 (m, 2H), 1.90(m, 2H), 1.80-1.10 (m, 13H), 1.00-0.84 (m, 6H).

EXAMPLE 3(23)

(2S)-N-[1-(2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)acetyl)cyclohexan-1-yl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

TLC: Rf 0.41 (ethyl acetate);

NMR (CDCl₃): δ 7.81 (m, 2H), 7.60-6.93 (m, 8H), 5.83 (brs, 1H), 4.30 (m,1H), 3.93 (d, J=14.7 Hz, 1H), 3.88 (d, J=14.7 Hz, 1H), 3.40 (m, 2H), 320-2.78 (m, 5H), 2.10-1.10 (m, 20H)

EXAMPLE 3(24)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(1,3-diazaspiro[4,5]decane-2,4-dion-3-yl)acetamide

TLC: Rf 0.32 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.25-7.00 (m, 4H), 6.76 and 6.66 (each d, J=8.0 Hz,totally 1H), 6.40 and 6.26 (each brs, totally 1H), 4.80-4.64 (m, 1H),4.25-4.04 (m, 2H), 3.98 (s, 2H), 3.38 (d, J=17.7 Hz, 1H), 3.29 (d,J=17.7 Hz, 1H), 3.24-3.10 (m, 2H), 2.97-2.83 (m, 2H), 2.03-1.20 (m,15H), 0.88 (d, J=6.3 Hz, 3H), 0.87 (d, J=6.3 Hz, 3H).

REFERENCE EXAMPLE 2

(1R,2S)-2-(t-butoxycarbonylamino)cyclohexylmethylalcohol

To a solution of (1R,2S)-2-aminocyclohexylmethylalcohol (500 mg) intetrahydrofuran (25 ml) was added di-t-butyl-dicarbonate (0.98 ml) andthe mixture was stirred for 1 hour at room temperature. The reactionmixture was concentrated and the residue was dried under reducedpressure to give the title compound (1.18 g) having the followingphysical data.

TLC: Rf 0.32 (n-hexane:ethyl acetate=3:1);

NMR (CD₃OD): δ 3.92-3.80 (br, 1H), 3.48-3.26 (m, 2H), 1.80-1.10 (m, 9H),1.44 (s, 9H).

REFERENCE EXAMPLE 3

(1R,2S)-2-(t-butoxycarbonylamino)cyclohexanecarbaldehyde

Under atmosphere of argon, to a solution of the compound prepared inreference example 2 (1.18 g) in dimethylsulfoxide (12 ml) were addedtriethylamine (1.62 ml) and sulfur trioxide-pyridine complex (1.85 g)under cooling with ice and the mixture was stirred for 1 hour at roomtemperature. The reaction mixture was poured into ice-water and wasextracted with ethyl acetate. The organic layer was washed with 10%aqueous solution of citric acid, water and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous magnesium sulfate,and was concentrated and the residue was dried under reduced pressure togive the title compound (810 mg) having the following physical data.

TLC: Rf 0.51 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 9.70 (d, J=1.5 Hz, 1H), 5.45-4.98 (br, 1H), 4.07-3.86 (m,1H), 2.82-2.58 (m, 1H), 2.06-1.85 (m, 1H), 1.82-1.19 (m, 7H), 1.43 (s,9H).

REFERENCE EXAMPLE 4

(1R,2S)-2-(t-butoxycarbonylamino)cyclohexanecarboxylic acid

To a solution of the compound prepared in reference example 3 (810 mg)in t-butanol (6.2 ml)-water (6.2 ml) were added 2-methyl-2-butene (1.85ml), sodium dihydrogenphosphate dihydrate (723 mg) and sodium chlorite(80%, 1.53 g) under cooling with ice and the mixture was stirred for 2hours at room temperature. To the reaction mixture was added 10% aqueoussolution of citric acid and was extracted with ethyl acetate. Theorganic layer was washed with 10% aqueous solution of citric acid, waterand a saturated aqueous solution of sodium chloride successively, driedover anhydrous magnesium sulfate and was concentrated. The residue waspurified by column chromatography on silica gel (n-hexane:ethylacetate=3:1) to give the title compound (734 mg) having the followingphysical data.

TLC: Rf 0.21 (n-hexane:ethyl acetate=3:1);

NMR (CD₃OD): δ 3.96-3.78 (m, 1H), 2.77-2.59 (m, 1H), 2.05-1.17 (m, 8H),1.43 (s, 9H)

EXAMPLE 4

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(t-butoxycarbonylamino)cyclohexyl]carboxamide

To a solution of the compound prepared in reference example 4 (374 mg)in dimethylformamide (5 ml) was added the compound prepared in example 2(243 mg) and 1-hydroxybenzotriazole (199 mg) and1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (211 mg)and triethylamine (0.28 ml) and the mixture was stirred for 4 hours atroom temperature. To the reaction mixture was added ethyl acetate andthe mixture was washed with a saturated aqueous solution of sodiumbicarbonate, water and a saturated aqueous solution of sodium chloridesuccessively, dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=2:1) to give the compound of thepresent invention (352 mg) having the following physical data.

TLC: Rf 0.24 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.25-6.97 (m, 4H), 6.22 and 6.07 (each d, J=8.1 Hz,totally 1H), 5.49 and 5.23 (each d, J=7.8 Hz, totally 1H), 4.75-4.60 (m,1H), 3.98 (s, 2H), 3.87-3.66 (m, 1H), 3.45-3.34 (m, 2H), 3.32-3.08 (m,2H), 3.00-2.80 (m, 2H), 2.67-2.53 (m, 1H), 2.08-1.15 (m, 13H), 1.43and1.41 (each s, totally 9H), 0.99-0.78 (m, 6H)

EXAMPLE 5

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-aminocyclohexyl]carboxamide dihydrochloride

By the same procedure as described in example 2 using the compoundprepared in example 4 in place of the compound prepared in example 1,the compound of the present invention having the following physical datawas obtained.

TLC: Rf 0.83 (chloroform:methanol:28% ammonia water=8:2:0.4);

NMR (CD₃OD): δ 7.46-7.09 (m, 4H), 4.62-4.15 (m, 5H), 3.75-3.54 (m, 2H),3.54-3.42 (m, 1H), 3.20-2.95 (m, 2H), 2.95-2.79 (m, 1H), 2.19-1.38 (m,13H), 0.98 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H).

EXAMPLE 6

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-chlorophenylcarbonylamino)cyclohexyl]carboxamide

To a suspension of the compound prepared in example 5 in dichloroethane(4 ml) was added triethylamine (0.33 ml) and the mixture was stirred for15 minutes at room temperature. Thereto was added 4-chlorobenzoylchloride (148 mg) and the mixture was stirred for another 4 hours. Tothe reaction mixture was added ethyl acetate and was washed with asaturated aqueous solution of sodium bicarbonate, water and a saturatedaqueous solution of sodium chloride successively. The organic layer wasdried over anhydrous magnesium sulfate and was concentrated. The residuewas purified by column chromatography on silica gel (ethylacetate:n-hexane=2:1) to give the compound of the present invention (284mg) having the following physical data.

TLC: Rf 0.51 (ethyl acetate);

NMR (CDCl₃): δ 7.79 and 7.71 (each d, J=9.0 Hz, totally 2H), 7.61 (d,J=9.0 Hz, 0.3H), 7.44-7.33 (m, 2.7H), 7.21-6.97 (m, 4H), 6.14 and 6.07(each d, J=8.4 Hz, totally 1H), 4.78-4.62 (m, 1H), 4.34-4.16 (m, 1H),4.04-3.86 (m, 2H), 3.38-3.20 (m, 2H), 3.20-3.07 (m, 2H), 3.02-2.83 (m,2H), 2.79-2.68 (m, 1H), 2.19-1.15 (m, 13H), 0.88, 0.87, 0.77 and 0.75(each d, J=6.6 Hz, totally 6H).

EXAMPLE 6(1)-EXAMPLE 6(27)

By the same procedure as described in example 6 using a halogenatedcompound corresponding to 4-chlorobenzoylchloride, the compound of thepresent invention having the following physical data was obtained.

EXAMPLE 6(1)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-phenylacetylaminocyclohexyl]carboxamide

TLC: Rf 0.66 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.35-7.00 (m, 9H), δ 63 and 6.44 (each d, J=8.4 and 8.1Hz, totally 1H), 6.08 (d, J=8.4 Hz, 1H), 4.70-4.50 (m, 1H), 4.20-4.00(m, 1H), 3.99 and 3.98 (each s, totally 2H), 3.65-3.45 (m, 2H),3.35-3.20 (m, 2H), 3.20-3.10 (m, 2H), 2.95-2.85 (m, 2H), 2.56 (q, J=5.2Hz, 1H), 1.90-1.15 (m, 13H), 0.90-0.75 (m, 6H).

EXAMPLE 6(2)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-hydrocinnamoylaminocyclohexyl]carboxamide

TLC: Rf 0.68 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.35-6.95 (m, 9H), 6.61 and 6.39 (each d, J=8.8 and 8.0Hz, totally 1H), 6.07 and 5.92 (each d, J=8.6 and 7.6 Hz, totally 1H),4.75-4.55 (m, 1H), 4.20-3.90 (m, 1H), 3.98 (s, 2H), 3.32 (s, 2H),3.25-3.10 (m, 2H), 3.05-2.75 (m, 4H), 2.60-2.35 (m, 3H), 2.00-1.10 (m,13H), 1.00-0.70 (m, 6H).

EXAMPLE 6(3)

N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-acetylaminocyclohexyl]carboxamide

TLC: Rf 0.62 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.40-7.00 (m, 4H), 6.65 and 6.43 (each d, J=8.8 and 8.2Hz, totally 1H), 6.15 (d, J=7.8 Hz, 1H), 4.75-4.55 (m, 1H), 4.20-3.95(m, 1H), 3.99 (s, 2H), 3.34 and 3.32 (each s, totally 2H), 3.25-3.10 (m,2H), 3.00-2.80 (m, 2H), 2.75-2.55 (m, 1H), 2.25-1.20 (m, 13H), 2.01 and1.93 (each s, totally 3H), 1.05-0.75 (m, 6H).

EXAMPLE 6(4)

N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(6-aminonicotinoyl)aminocyclohexyl]carboxamide

TLC: Rf 0.40 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.57 and 8.49 (each d, J=2.0 Hz, totally 1H), 7.92 and7.83 (each dd, J=8.8 and 2.0 Hz, totally 1H), 7.60-7.30 (m, 1H),7.25-6.95 (m, 4H), 6.47 and 6.44 (each d, J=8.8 Hz, totally 1H),6.24-6.00 (m, 1H), 4.89 (brs, 2H), 4.85-4.54 (m, 1H), 4.40-4.13 (m, 1H),3.98 and 3.95 (each s, totally 2H), 3.32 (s, 2H), 3.25-3.04 (m, 2H),3.00-2.83 (m, 2H), 2.83-2.62 (m, 1H), 2.19-1.08 (m, 13H), 0.87, 0.86,0.78, and 0.76 (each d, J=6.4 Hz, totally 6H)

EXAMPLE 6(5)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-(t-butoxycarbonyl)piperazin-1-ylcarbonylamino)cyclohexyl]carboxamide

TLC: Rf 0.38 (ethyl acetate);

NMR (CDCl₃): δ 7.23-6.98 (m, 4H), 6.16 (d, J=8.7 Hz, 1H), 5.76 (d, J=7.7Hz, 1H), 4.75-4.63 (m, 1H), 4.02-3.86 (m, 1H), 3.97 (brs, 2H), 3.48-3.36(m, 4H), 3.36-3.25 (m, 4H), 3.32 (s, 2H), 3.22-3.12 (m, 2H), 2.96-2.86(m, 2H), 2.70-2.57 (m, 1H), 2.03-1.24 (m, 13H), 1.46 (s, 9H), 0.87 (d,J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H).

EXAMPLE 6(6)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(quinoxalin-2-ylcarbonylamino)cyclohexyl]carboxamide

TLC: Rf 0.44 (ethyl acetate);

NMR (CDCl₃): δ 9.65 and 9.64 (each s, totally 1H), 8.77 and 8.63 (eachd, J=8.4 Hz, totally 1H), 8.24-8.10 (m, 2H), 7.94-7.76 (m, 2H),7.25-6.87 (m, 4H), 6.25 and 6.12 (each d, J=8.4 Hz, totally 1H),4.78-4.63 (m, 1H), 4.51-4.32 (m, 1H), 3.96 and 3.83 (each s, totally2H), 3.34-3.18 (m, 2H), 3.18-3.10 and 3.04-2.85 (each m, totally 4H),2.85-2.73 (m, 1H), 2.34-1.10 (m, 13H), 0.86, 0.85, 0.62 and 0.58 (eachd, J=6.3 Hz, totally 6H).

EXAMPLE 6(7)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-naphthoylaminocyclohexyl]carboxamide

TLC: Rf 0.47 (ethyl acetate);

NMR (CDCl₃): δ 8.39 and 8.29 (each s, totally 1H), 7.99-7.79 (m, 4H),7.70 and 7.43 (each d, J=7.5 Hz, totally 1H), 7.61-7.48 (m, 2H),7.22-6.89 (m, 4H), 6.17 and 6.11 (each d, J=8.4 Hz, totally 1H),4.79-4.61 (m, 1H), 4.44-4.26 (m, 1H), 4.03-3.88 (m, 2H), 3.37-3.22 (m,2H), 3.21-3.05 (m, 2H), 3.01-2.87 (m, 2H), 2.87-2.76 (m, 1H), 2.20-1.10(m, 13H), 0.86, 0.85, 0.72 and 0.71 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 6(8)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(1-benzothiophen-2-ylcarbonylamino)cyclohexyl]carboxamide

TLC: Rf 0.56 (ethyl acetate);

NMR (CDCl₃): δ 7.90-7.75 (m, 2H), 7.72 (s, 1H), 7.45-7.31 (m, 3H),7.23-6.94 (m, 4H), 6.14 and 6.08 (each d, J=8.1 Hz, totally 1H),4.79-4.62 (m, 1H), 4.36-4.16 (m, 1H), 4.02-3.88 (m, 2H), 3.33 (s, 2H),3.22-3.06 (m, 2H), 3.02-2.81 (m, 2H), 2.81-2.72 (m, 1H), 2.20-1.12 (m,13H), 0.87, 0.86, 0.76 and 0.75 (each d, J=6.3 Hz, totally 6H)

EXAMPLE 6(9)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-methoxybenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.43 (ethyl acetate);

NMR (CDCl₃): δ 7.81 and 7.73 (each d, J=9.0 Hz, totally 2H), 7.44 (d,J=8.4 Hz, 0.3H), 7.23-6.95 (m, 4.7H), 6.90 (d, J=9.0 Hz, 2H), 6.14 and6.10 (each d, J=8.4 Hz, totally 1H), 4.76-4.60 (m, 1H), 4.34-4.18 (m,1H), 3.97 and 3.93 (each brs, totally 2H), 3.84 and 3.83 (each s,totally 3H), 3.37-3.21 (m, 2H), 3.21-3.06 (m, 2H), 3.01-2.82 (m, 2H),2.80-2.69 (m, 1H), 2.18-1.12 (m, 13H), 0.87, 0.75 and 0.74 (each d,J=6.3 Hz, totally 6H).

EXAMPLE 6(10)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-nitrobenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.51 (ethyl acetate);

NMR (CDCl₃): δ 8.31-8.21 (m, 2H), 8.01 and 7.94 (each d, J=9.0 Hz,totally 2H), 7.85 and 7.76 (each d, J=7.5 Hz, totally 1H), 7.23-6.96 (m,4H), 6.17 and 6.08 (each d, J=8.4 Hz, totally 1H), 4.80-4.66 (m, 1H),4.36-4.18 (m, 1H), 4.06-3.88 (m, 2H), 3.40-3.24 (m, 2H), 3.24-3.07 (m,2H), 3.02-2.84 (m, 2H), 2.80-2.70 (m, 1H), 2.20-1.20 (m, 13H), 0.89,0.88, 0.80 and 0.78 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 6(11)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-phenylbenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.33 (ethyl acetate);

NMR (CDCl₃): δ 7.92 and 7.84 (each d, J=9.0 Hz, totally 2H), 7.70-7.55(m, 4H), 7.51-7.30 (m, 4H), 7.23-6.97 (m, 4H), 6.20-6.09 (m, 1H),4.79-4.63 (m, 1H), 4.42-4.20 (m, 1H), 3.98 and 3.95 (each s, totally2H), 3.40-3.21 (m, 2H), 3.21-3.03 (m, 2H), 3.03-2.81 (m, 2H), 2.81-2.69(m, 1H), 2.20-1.12 (m, 13H), 0.87 and 0.76 (each d, J=6.6 Hz, totally6H).

EXAMPLE 6(12)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.36 (ethyl acetate);

NMR (CDCl₃): δ 7.89-7.73 (m, 2H), 7.57 and 7.33 (each d, J=8.1 Hz,totally 1H), 7.22-6.97 (m, 6H), 6.13 and 6.08 (each d, J=8.1 Hz, totally1H), 4.77-4.62 (m, 1H), 4.34-4.16 (m, 1H), 3.98 and 3.95 (each s,totally 2H), 3.32 (s, 2H), 3.23-3.08 (m, 2H), 3.03-2.84 (m, 2H),2.79-2.67 (m, 1H), 2.15-1.16 (m, 13H), 0.88, 0.87, 0.77 and 0.75 (eachd, J=6.6 Hz, totally 6H).

EXAMPLE 6(13)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-pyridylcarbonylamino)cyclohexyl]carboxamide

TLC: Rf 0.28 (ethyl acetate);

NMR (CDCl₃): δ 8.60 (d. J=8.4 Hz, 1H), 8.55 (ddd, J=5.0, 2.0 and 1.2 Hz,1H), 8.14 (dt, J=7.8 and 1.2 Hz, 1H), 7.82 (dt, J=2.0 and 7.8 Hz, 1H),7.40 (ddd, J=7.8, 5.0 and 1.2 Hz, 1H), 7.23-6.96 (m, 4H), 6.17 (d, J=8.4Hz, 1H), 4.72-4.59 (m, 1H), 4.44-4.30 (m, 1H), 3.96 (s, 2H), 3.34 (d,J=18.3 Hz, 1H), 3.27 (d, J=18.3 Hz, 1H), 3.20-3.08 (m, 2H), 2.96-2.83(m, 2H), 2.79-2.68 (m, 1H), 2.20-1.10 (m, 13H), 0.65 and 0.63 (each d,J=6.0 Hz, totally 6H)

EXAMPLE 6(14)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-t-butylbenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.39 (ethyl acetate);

NMR (CDCl₃): δ 7.77 and 7.70 (each d, J=9.0 Hz, totally 2H), 7.49 (d,J=8.0 Hz, 0.3H), 7.42 (d, J=9.0 Hz, 2H), 7.25-6.94 (m, 4.7H), 6.14 (d,J=8.4 Hz, 1H), 4.74-4.60 (m, 1H), 4.36-4.20 (m, 1H), 3.98 and 3.95 (eachs, totally 2H), 3.33 and 3.30 (each s, totally 2H), 3.22-3.07 (m, 2H),3.00-2.84 (m, 2H), 2.79-2.69 (m, 1H), 2.15-1.18 (m, 13H), 1.32 and 1.31(each s, totally 9H), 0.86 and 0.74 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 6(15)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-methylthionicotinoylamino)cyclohexyl]carboxamide

TLC: Rf 0.32 (ethyl acetate);

NMR (CDCl₃): δ 8.53-8.44 (m, 1H), 7.78 and 7.73 (each dd, J=7.7 and 1.7Hz, totally 1H), 7.45 (d, J=9.6 Hz, 0.3H), 7.25-6.92 (m, 5.7H), 6.19 and6.12 (each d, J=8.4 Hz, totally 1H), 4.74-4.58 (m, 1H), 4.40-4.24 (m,1H), 4.01-3.82 (m, 2H), 3.31 and 3.27 (each s, totally 2H), 3.21-3.06(m, 2H), 3.01-2.84 (m, 2H), 2.81-2.70 (m, 1H), 2.54 (s, 3H), 2.20-1.20(m, 13H), 0.88, 0.85, 0.80 and 0.77 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 6(16)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(1-naphthylacetylamino)cyclohexyl]carboxamide

TLC: Rf 0.29 (ethyl acetate);

NMR (CDCl₃): δ 8.07-7.92 (m, 1H), 7.89-7.74 (m, 2H), 7.55-7.30 (m, 4H),7.22-6.97 (m, 4H), 6.58 and 6.41 (each d, J=8.7 Hz, totally 1H), 6.05(br, 0.3H), 6.00 (d, J=7.8 Hz, 0.7H), 4.60-4.45 (m, 1H), 4.21-3.76 (m,5H), 3.27 (s, 2H), 3.20-3.08 (m, 2H), 3.01-2.85 (m, 2H), 2.54-2.39 (m,1H), 1.90-1.05 (m, 13H), 0.89, 0.86, 0.85 and 0.81 (each d, J=6.3 Hz,totally 6H).

EXAMPLE 6(17)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-fluorobenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.42 (ethyl acetate);

NMR (CDCl₃): δ 8.07-7.98 (m, 1H), 7.83-7.65 and 7.65-7.34 (each m,totally 2H), 7.30-6.94 (m, 6H), 6.21 and 6.11 (each d, J=8.4 Hz, totally1H), 4.77-4.63 (m, 1H), 4.46-4.28 (m, 1H), 3.96 and 3.91 (each s,totally 2H), 3.40-3.21 (m, 2H), 3.21-3.04 (m, 2H), 2.96-2.82 (m, 2H),2.80-2.68 (m, 1H), 2.20-1.16 (m, 13H), 0.88, 0.87 and 0.72 (each d,J=6.3 Hz, totally 6H).

EXAMPLE 6(18)

N-[(3S)-1-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-(6-chloronicotinoylamino)cyclohexyl]carboxamide

TLC: Rf 0.32 (ethyl acetate);

NMR (CDCl₃): δ 8.85 and 8.77 (each d, J=2.7 Hz, totally 1H), 8.12 and8.04 (each dd, J=8.4 and 2.7 Hz, totally 1H), 7.80 and 7.71 (each d,J=7.5 Hz, totally 1H), 7.38 and 7.37 (each d, J=8.4 Hz, totally 1H),7.23-6.95 (m, 4H), 6.14 and 6.03 (each d, J=8.4 Hz, totally 1H),4.81-4.64 (m, 1H), 4.34-4.15 (m, 1H), 4.06-3.85 (m, 2H), 3.32 and 3.31(each s, totally 2H), 3.24-3.07 (m, 2H), 3.02-2.84 (m, 2H), 2.79-2.66(m, 1H), 2.15-1.17 (m, 13H), 0.89, 0.87, 0.81 and 0.79 (each d, J=6.3Hz, totally 6H).

EXAMPLE 6(19)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-trifluoromethylbenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.41 (ethyl acetate);

NMR (CDCl₃): δ 7.96 and 7.88 (each d, J=8.1 Hz, totally 2H), 7.68 (d,J=8.1 Hz, 2H), 7.57 (d, J=7.5 Hz, 1H), 7.24-6.96 (m, 4H), 6.15 (d, J=7.8Hz, 1H), 4.78-4.65 (m, 1H), 4.35-4.18 (m, 1H), 4.06-3.90 (m, 2H), 3.33(s, 2H), 3.25-3.04 (m, 2H), 3.04-2.84 (m, 2H), 2.80-2.67 (m, 1H),2.18-1.20 (m, 13H), 0.88, 0.87, 0.78 and 0.76 (each d, J=6.6 Hz, totally6H).

EXAMPLE 6(20)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.36 (ethyl acetate);

NMR (CDCl₃): δ 7.95 and 7.88 (each d, J=9.0 Hz, totally 2H), 7.77-7.64(m, 3H), 7.24-6.96 (m, 4H), 6.16 and 6.09 (each d, J=8.4 Hz, totally1H), 4.79-4.65 (m, 1H), 4.32-4.17 (m, 1H), 4.05-3.90 (m, 2H), 3.32 and3.31 (each s, totally 2H), 3.25-3.04 (m, 2H), 3.04-2.82 (m, 2H),2.77-2.65 (m, 1H), 2.18-1.18 (m, 13H), 0.89, 0.88, 0.79 and 0.77 (eachd, J=6.3 Hz, totally 6H).

EXAMPLE 6(21)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-methylbenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.32 (ethyl acetate);

NMR (CDCl₃): δ 7.73 and 7.65 (each d, J=8.1 Hz, totally 2H), 7.49 (d,J=7.8 Hz, 0.2H), 7.24-6.96 (m, 6.8H), 6.15 (d, J=8.4 Hz, 1H), 4.76-4.61(m, 1H), 4.34-4.19 (m, 1H), 3.98 and 3.94 (each s, totally 2H),3.43-3.21 (m, 2H), 3.21-3.05 (m, 2H), 3.03-2.81 (m, 2H), 2.81-2.67 (m,1H), 2.38 (s, 3H), 2.22-1.15 (m, 13H), 0.86, 0.75 and 0.74 (each d,J=6.6 Hz, totally 6H)

EXAMPLE 6(22)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-trifluoromethyloxybenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.41 (ethyl acetate);

NMR (CDCl₃): δ 7.90 and 7.82 (each d, J=8.7 Hz, total 2H), 7.65 and 7.44(each d, J=7.8 Hz, total 1H), 7.34-6.93 (m, 6H), 6.15 (d, J=8.1 Hz, 1H),4.78-4.62 (m, 1H), 4.34-4.17 (m, 1H), 4.06-3.90 (m, 2H), 3.33 (s, 2H),3.25-3.06 (m, 2H), 3.03-2.82 (m, 2H), 2.82-2.65 (m, 1H), 2.20-1.15 (m,13H), 0.87, 0.77 and 0.75 (each d, J=6.3 Hz, total 6H).

EXAMPLE 6(23)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(3-t-butyl-1-methylpyrazol-5-ylcarbonylamino)cyclohexyl]carboxamide

TLC: Rf 0.42 (ethyl acetate);

NMR (CDCl₃): δ 7.37 (d, J=9.0 Hz, 0.2H), 7.22-6.98 (m, 4.8H), 6.49 and6.31 (each s, total 1H), 6.12 and 6.05 (each d, J=8.1 Hz, total 1H),4.80-4.64 (m, 1H), 4.28-4.05 (m, 1H), 4.12 and 4.09 (each s, total 3H),4.05-3.90 (m, 2H), 3.33 (s, 2H), 3.24-3.08 (m, 2H), 3.03-2.84 (m, 2H),2.80-2.65 (m, 1H), 2.15-1.13 (m, 13H), 1.29 and 1.28 (each s, total 9H),0.88, 0.87, 0.80 and 0.79 (each d, J=6.3 Hz, total 6H).

EXAMPLE 6(24)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(N,N-di-n-propyl-4-sulfamoyl)benzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.42 (ethyl acetate);

NMR (CDCl₃): δ 7.89 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.7 Hz, 2H), 7.60 (d,J=7.8 Hz, 1H), 7.25-6.96 (m, 4H), 6.19 (d, J=8.4 Hz, 1H), 4.80-4.66 (m,1H), 4.36-4.18 (m, 1H), 3.99 (s, 2H), 3.34 (s, 2H), 3.25-3.13 (m, 2H),3.13-3.00 (m, 4H), 2.97-2.84 (m, 2H), 2.80-2.68 (m, 1H), 2.13-1.20 (m,17H), 0.87 (t, J=7.5 Hz, 6H), 0.79 and 0.76 (each d, J=6.3 Hz, total6H).

EXAMPLE 6(25)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-mesylaminocyclohexyl]carboxamide

TLC: Rf 0.39 (ethyl acetate);

NMR (CDCl₃): δ 7.24-6.99 (m, 4H), 6.30 and 5.64 (each d, J=7.5 Hz, total1H), 6.08 (d, J=8.1 Hz, 1H), 4.77-4.62 (m, 1H), 3.97 (s, 2H), 3.74-3.56(m, 1H), 3.34 and 3.32 (each s, total 2H), 3.22-3.12 (m, 2H), 3.00-2.85(m, 2H), 2.98and 2.92 (each s, total 3H), 2.76-2.59 (m, 1H), 2.17-1.20(m, 13H), 0.96-0.80 (m, 6H).

EXAMPLE 6(26)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-phenylsulfonylaminocyclohexyl]carboxamide

TLC: Rf 0.58 (ethyl acetate);

NMR (CDCl₃): δ 7.92-7.82 (m, 2H), 7.60-7.40 (m, 3H), 7.23-6.98 (m, 4H),6.14 (d, J=6.6 Hz, 1H), 6.11-5.96 (br, 1H), 4.71-4.56 (m, 1H), 4.00 (s,2H), 3.52-3.24 (brs, 3H), 3.24-3.11 (m, 2H), 3.02-2.83 (m, 2H),2.52-2.40 (m, 1H), 2.02-1.17 (m, 13H), 0.88 and 0.86 (each d, J=6.3 Hz,total 6H).

EXAMPLE 6(27)

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]carboxamide

TLC: Rf 0.19 (ethyl acetate);

NMR (CDCl₃): δ 7.75 and 7.66 (each d, J=9.2 Hz, total 2H), 7.32-7.24 and7.22-6.87 (each m, total 5H), 6.65 (d, J=9.2 Hz, 2H), 6.23-6.04 (m, 1H),4.77-4.54 (m, 1H), 4.40-4.16 (m, 1H), 3.97 and 3.93 (each brs, total2H), 3.39-3.22 (m, 2H), 3.22-3.04 (m, 2H), 3.00 and 2.99 (each s, total6H), 2.97-2.81 (m, 2H), 2.81-2.65 (m, 1H), 2.17-1.14 (m, 13H), 0.86 and0.73 (each d, J=6.0 Hz, total 6H).

EXAMPLE 7

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(piperazin-1-ylcarbonylamino)cyclohexyl]carboxamide dihydrochloride

By the same procedure as described in example 2 using the compoundprepared in example 6 (5) in place of the compound prepared in example1, the compound of the present invention having the following physicaldata was obtained.

TLC: Rf 0.22 (chloroform:methanol:acetic acid=10:2:1);

NMR (CD₃OD): δ 7.48-7.20 (m, 4H), 4.47 (brs, 2H), 4.34 (dd, J=10.2 and4.8 Hz, 1H), 4.31-4.01 (m, 3H), 3.71-3.47 (m, 6H), 3.19 (t, J=5.4 Hz,4H), 3.12-3.01 (m, 2H), 2.75-2.56 (m, 1H), 2.18-1.16 (m, 13H), 0.96 (d,J=6.3 Hz, 3H), 0.88 (d, J=6.3 Hz, 3H).

EXAMPLE 8

(3S)-3-(t-butoxycarbonylamino)-5-methyl-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)hexan-2-one

To a solution of the compound prepared in Reference Example 1 (3.08 g)and 2,3,4,5-tetrahydro-1H-1-benzazepine (2.21 g) in acetonitrile (28 ml)was added diisopropylethylamine (2.61 ml) at 0° C. and the mixture wasstirred at room temperature for 62 hours. To the reaction mixture wasadded water and was extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and was concentrated. The residue was purifiedby column chromatography on silica gel (n-hexane:ethyl acetate=10:1) togive the compound of the present invention (3.16 g) having the followingphysical data.

TLC: Rf 0.50 (n-hexane:ethyl acetate 7:3);

NMR (CDCl₃): δ 7.11 (d, J=7.2 Hz, 1H), 7.10 (t, J=7.2 Hz, 1H), 6.88 (t,J=7.2 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 5.00 (d, J=8.4 Hz, 1H), 4.59 (m,1H), 4.15 (d, J=15.3 Hz, 1H), 4.10 (d, J=15.3 Hz, 1H), 3.00-2.80 (m,4H), 1.89-1.30 (m, 4H), 1.43 (s, 9H), 0.96 (d, J=6.3 Hz, 3H), 0.90 (d,J=6.3 Hz, 3H)

EXAMPLE 9

(3S)-3-amino-5-methyl-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)hexan-2-onedihydrochloride

By the same procedure as described in example 2 using the compoundprepared in example 8 in place of the compound prepared in example 1,the compound of the present invention having the following physical datawas obtained as a crude product. The crude product was used in the nextreaction without further purification.

TLC: Rf 0.35 (chloroform:methanol:water=10:1:0.1).

EXAMPLE 10-EXAMPLE 10 (9)

By the same procedure as described in example 3 using the compoundprepared in example 9 in place of the compound prepared in example 2 and(−)-2-benzamidocyclohexanecarboxylic acid or a corresponding carboxylicacid thereto, the compound of the present invention having the followingphysical data was obtained.

EXAMPLE 10

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

TLC: Rf 0.35 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.78 (dd, J=7.6, 1.8 Hz, 1H), 7.50-7.36 (m, 3H), 7.24 (d,J=9.6 Hz, 1H), 7.14-7.06 (m, 2H), 6.89 (dt, J=1.8, 7.6 Hz, 1H), 6.75 (d,J=7.6 Hz, 1H), 6.13 (d, J=8.4 Hz, 1H), 4.96 (dt, J=3.4, 8.4 Hz, 1H),4.29 (m, 1H), 4.16 (d, J=17.2 Hz, 1H), 4.08 (d, J=17.2 Hz, 1H),3.00-2.68 (m, 4H), 2.20-2.00 (m, 1H), 2.00-1.10 (m, 15H), 0.82 (d, J=6.0Hz, 3H), 0.76 (d, J=6.0 Hz, 3H).

EXAMPLE 10(1)

(2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.50 (chloroform:ethyl acetate=9:1);

NMR (CDCl₃): δ 7.34 (m, 5H), 7.10 (m, 2H), 6.89 (dt, J=0.9, 7.5 Hz, 1H),6.74 (d, J=7.5 Hz, 1H), 6.38 (brd, J=8.4 Hz, 1H), 5.10 (m, 3H), 4.96(ddd, J=9.9, 8.4, 3.9 Hz, 1H), 4.20-4.00 (m, 3H), 3.02-2.78 (m, 2H),1.92-1.60 (m, 10H), 1.00-0.85 (m, 12H).

EXAMPLE 10(2)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-1-cyclohexylcarboxamide

TLC: Rf 0.70 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.11 (d, J=7.2 Hz, 1H), 7.10 (dt, J=1.8, 7.2 Hz, 1H),6.89 (dt, J=1.8, 7.2 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 5.87 (d, J=8.4 Hz,1H), 4.97 (ddd, J=10.2, 8.4, 3.9 Hz, 1H), 4.14 (d, J=17.4 Hz, 1H), 4.06(d, J=17.4 Hz, 1H), 3.05-2.77 (m, 4H), 2.09 (tt, J=11.4, 3.3 Hz, 1H),1.90-1.20 (m, 17H), 0.95 (d, J=6.3 Hz, 3H) and 0.90 (d, J=6.3 Hz, 3H).

EXAMPLE 10(3)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-4-benzyloxybenzamide

TLC: Rf 0.60 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.73 (d, J=8.7 Hz, 2H), 7.48-7.32 (m, 5H), 7.14-7.08 (m,2H), 6.99 (d, J=8.7 Hz, 2H), 6.89 (dt, J=1.8, 7.6 Hz, 1H), 6.78 (d,J=7.6 Hz, 1H), 6.54 (d, J=8.7 Hz, 1H), 5.20 (m, 1H), 5.11 (s, 2H), 4.22(d, J=17.1 Hz, 1H), 4.18 (d, J=17.1 Hz, 1H), 3.18-2.78 (m, 4H),1.99-1.43 (m, 7H), 1.00 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).

EXAMPLE 10(4)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-3-benzyloxybenzamide

TLC: Rf 0.65 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.50-7.20 and 7.20-7.05 (each m, totally 11H), 6.90 (dt,J=1.8, 7.6 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H),5.30-5.18 (m, 1H), 5.11 (s, 2H), 4.20 (d, J=17.2 Hz, 1H), 4.13 (d,J=17.2 Hz, 1H), 3.10-2.80 (m, 4H), 1.95-1.40 (m, 7H), 1.02 (d, J=6.2 Hz,3H), 0.93 (d, J=6.2 Hz, 3H).

EXAMPLE 10(5)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-2-benzyloxybenzamide

TLC: Rf 0.55 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 8.26 (d, J=7.2 Hz, 1H), 8.21 (dd, J=7.8, 1.8 Hz, 1H),7.52-7.38 (m, 6H), 7.13-7.05 (m, 4H), 6.85 (t, J=7.2 Hz, 1H), 6.73 (d,J=7.2 Hz, 1H), 5.19 (d, J=10.5 Hz, 1H), 5.16 (d, J=10.5 Hz, 1H),4.96-4.89 (m, 1H), 4.19 (d, J=17.7 Hz, 1H), 4.12 (d, J=17.7 Hz, 1H),3.09-2.72 (m, 4H), 1.90-1.05 (m, 7H), 0.82 (d, J=6.0 Hz, 3H), 0.67 (d,J=6.0 Hz, 3H)

EXAMPLE 10(6)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide

TLC: Rf 0.25 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.80 (dd, J=8.4, 1.8 Hz, 2H), 7.51-7.36 and 7.13-7.00(each m, totally 6H), 6.89 (dt, J=18, 8.0 Hz, 1H), 6.72 (d, J=8.0 Hz,1H), 6.07 (d, J=8.4 Hz, 1H), 4.91 (ddd, J=10.4, 8.4, 4.4 Hz, 1H), 4.29(m, 1H), 4.11 (d, J=17.2 Hz, 1H), 4.05 (d, J=17.2 Hz, 1H), 2.98-2.69 (m,4H), 2.10-1.25 (m, 16H), 0.94 (d, J=6.2 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H).

EXAMPLE 10(7)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]benzamide

TLC: Rf 0.60 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.78 (dd, J=8.4, 1.8 Hz, 2H), 7.54-7.38 (m, 3H) 7.15-7.07(m, 2H), 6.90 (t, J=7.4 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 6.64 (d, J=8.0Hz, 1H), 5.23 (dt, J=4.0, 8.0 Hz, 1H), 4.22 (d, J=16.8 Hz, 1H), 4.14 (d,J=16.8 Hz, 1H), 3.10-2.77 (m, 4H), 1.95-1.43 (m, 7H), 1.02 (d, J=6.0 Hz,3H), 0.93 (d, J=6.0 Hz, 3H).

EXAMPLE 10(8)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-3-cyclopentylpropanamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.14-7.06 (m, 2H), 6.88 (dt, J=1.8, 8.0 Hz, 1H), 6.75 (d,J=8.0 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 5.00 (ddd, J=9.8, 8.0, 4.0 Hz,1H), 4.15 (d, J=17.2 Hz, 1H), 4.08 (d, J=17.2 Hz, 1H), 3.08-2.80 (m,4H), 2.20 (dd, J=9.0, 7.6 Hz, 2H), 1.90-1.30 and 1.20-1.00 (each m,totally 18H), 0.95 (d, J=6.4 Hz, 3H), 0.90 (d, J=6.4 Hz, 3H).

EXAMPLE 10(9)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]cinnamide

TLC: Rf 0.60 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.62 (d, J=15.6 Hz, 1H), 7.50-7.47 and 7.39-7.34 (each m,totally 5H), 7.14-7.09 (m, 2H), 6.88 (dt, J=1.8, 8.1 Hz, 1H), 6.79 (d,J=8.1 Hz, 1H), 6.41 (d, J=15.6 Hz, 1H), 6.16 (d, J=8.4 Hz, 1H), 5.18(ddd, J=10.2, 8.4, 4.2 Hz, 1H), 4.15 (d, J=17.1 Hz, 1H), 4.12 (d, J=17.1Hz, 1H), 3.08-2.78 (m, 4H), 1.98-1.38 (m, 7H), 1.00 (d, J=6.6 Hz, 3H),0.91 (d, J=6.6 Hz, 3H).

EXAMPLE 11

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzenesulfonamide

To a solution of the compound prepared in example 2 (137 mg) indimethylformamide (2 ml) were added benzenesulfonyl chloride (0.07 ml)and triethylamine (0.08 ml) dropwise and the mixture was stirred for 55hours at room temperature. To the reaction mixture was added 10% aqueoussolution of citric acid and was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumbicarbonate, water and a saturated aqueous solution of sodium chloridesuccessively, dried over anhydrous sodium sulfate and was concentrated.The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the compound of the presentinvention (10.1 mg) having the following physical data.

TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.84 (dd, J=8.7, 1.8 Hz, 2H), 7.60-7.47 (m, 3H),7.20-7.05 (m, 3H), 6.85 (d, J=6.9 Hz, 1H), 5.90-5.30 (br, 1H), 4.08 (dd,J=9.6, 4.2 Hz, 1H), 3.82 (d, J=15.0 Hz, 1H), 3.65 (d, J=15.0 Hz, 1H),3.09 (d, J=18.0 Hz, 1H), 3.05 (d, J=18.0 Hz, 1H), 2.91-2.84 (m, 4H),1.80-1.50 and 1.40-1.20 (each m, totally 5H), 0.84 (d, J=6.6 Hz, 3H),0.75 (d, J=6.6 Hz, 3H).

EXAMPLE 11(1)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]benzenesulfonamide

By the same procedure as described in example 11 using the compoundprepared in example 9 in place of the compound prepared in example 2,the compound of the present invention having the following physical datawas obtained.

TLC: Rf 0.50 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.78 (dd, J=6.9, 1.8 Hz, 2H), 7.56-7.42 (m, 3H) 7.10 (dd,J=7.2, 1.8 Hz, 1H), 7.05 (dt, J=1.8, 7.2 Hz, 1H), 6.90 (dt, J=1.8, 7.2Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 5.47 (d, J=9.3 Hz, 1H), 4.24 (dt,J=3.9, 9.3 Hz, 1H), 3.92 (d, J=17.4 Hz, 1H), 3.81 (d, J=17.4 Hz, 1H),2.85-2.50 (m, 4H), 1.90-1.20 (m, 7H), 0.84 (d, J=6.6 Hz, 6H)

REFERENCE EXAMPLE 5

7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-1-one

To a solution of 6-hydroxy-1-tetralone (6.5 g) in methanesulfonic acid(140 ml) was added sodium azide (3.4 g) under cooling with ice and themixture was stirred for 30 minutes at 0° C. and for 15 hours at roomtemperature. The reaction mixture was poured into ice-water and theretowas added potassium carbonate to alkalify and was extracted withmethylene chloride. The organic layer was washed with water, a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous magnesium sulfateand was concentrated to give the title compound having the followingphysical data as a crude product. The crude product was used in the nextreaction without further purification.

TLC: Rf 0.39 (chloroform:methanol=9:1).

REFERENCE EXAMPLE 6

7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-1-one

Under atmosphere of argon, to a solution of the compound prepared inreference example 5 (4.79 g) in dimethylformamide (60 ml) were addedpotassium carbonate (11.2 g) and benzyl bromide (3.57 ml) at 0° C. andthe mixture was stirred for 30 minutes at room temperature. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with water, a saturated aqueous solution ofsodium bicarbonate and a saturated aqueous solution of sodium chloridesuccessively, and was dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:n-hexane=3:1) to give the title compound (3.8g) having the following physical data.

TLC: Rf 0.48 (chloroform:methanol=19:1);

NMR (CDCl₃): δ 7.67 (d, J=8.4 Hz, 1H), 7.50-7.30 (m, 5H), 6.92 (dd,J=8.4, 2.6 Hz 1H), 6.80 (d, J=2.6 Hz, 1H), 6.20 (m, 1H), 5.10 (s, 2H),3.14 (m, 2H), 2.84 (t, J=7.0 Hz, 2H), 2.01 (quintet, J=7.0 Hz, 2H).

REFERENCE EXAMPLE 7

7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin hydrochloride

To a solution of the compound prepared in reference example 6 (3.75 g)in tetrahydrofuran (30 ml) was added a suspension of lithium alminumhydride (1.86 g) in tetrahydrofuran (90 ml) at 0° C. and the mixture wasstirred for 4 hours at 80° C. To the reaction mixture was addedice-water and 15% aqueous solution of sodium hydroxide and the mixturewas filtered. To the filtrate was added water and was extracted withmethylene chloride. The organic layer was washed with water and asaturated aqueous solution of sodium chloride successively, dried overanhydrous magnesium sulfate to give the title compound having thefollowing physical data as a free compound (3.5 g). A solution thereofin ethyl acetate (20 ml) was added 4N hydrochloric acid-ethyl acetate(20 ml) at 0° C. and the mixture was stirred for 30 minutes at roomtemperature. The reaction mixture was concentrated and the residue waswashed with diethyl ether to give the title compound having thefollowing physical data.

NMR (DMSO-d₆): δ 8.84 (m, 1H), 7.45-7.24 (m, 6H, O), 6.94 (d, J=2.7 Hz,1H), 6.84 (dd, J=8.4, 2.7 Hz, 1H), 5.11 (s, 2H), 4.23 (s, 2H), 3.30 (m,2H), 1.82 (m, 2H).

EXAMPLE 12

1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone

To a solution of the compound prepared in reference example 7 (2.9 g) ina suspension of acetonitrile (30 ml) was added diisopropylethylamine(5.22 ml) and the compound prepared in reference example 1 (3.1 g)successively and the mixture was stirred for 30 minutes at roomtemperature. To the reaction mixture was added water and was extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous magnesium sulfateand was concentrated. The residue was purified by column chromatographyon silica gel (n-hexane:ethyl acetate=2:1) to give the compound of thepresent invention (4.4 g) having the following physical data.

TLC: Rf 0.31 (hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.45-7.30 (m, 5H), 6.97 (d, J=8.1 Hz, 1H), 6.80 (d, J=2.7Hz, 1H), 6.60 (dd, J=8.1, 2.7 Hz, 1H), 5.05 (s, 2H), 4.98 (brd, J=8.4Hz, 1H), 4.38 (m, 1H), 3.94 (s, 2H), 3.33 (brs, 2H), 3.16 (t, J=5.1 Hz,2H), 2.85 (t, J=5.4 Hz, 2H), 1.85-1.60 (m, 5H), 1.43 (s, 9H), 0.94-0.88(d, J=6.6 Hz, 6H)

EXAMPLE 13

3-amino-1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-hexanonedihydrochloride

By the same procedure as described in example 2 using the compoundprepared in example 12 in place of the compound prepared in example 1,the compound of the present invention having the following physical datawas obtained.

TLC: Rf 0.56 (chloroform:methanol:acetic acid=9:1:1).

EXAMPLE 14

(2S)-N-[(3S)-1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

To a suspension of the compound prepared in reference example 7 (145 mg)in acetonitrile (3 ml) was added diisopropylethylamine (0.19 ml) at 0°C. and then was added(2S)-N-[(3S)-1-bromo-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide(250 mg) and the mixture was stirred for 2 hours at room temperature. Tothe reaction mixture was added water and was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium bicarbonate and a saturated aqueous solution of sodiumchloride successively, dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=7:3) to give the compound of thepresent invention (242 mg) having the following physical data.

TLC: Rf 0.31 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.48-7.23 (m, 10H), 6.94 (m, 1H), 6.79 (d, J=2.7 Hz, 1H),6.68 (dd, J=8.4, 2.7 Hz, 1H), 6.37 (brd, J=8.1 Hz, 1H), 5.20-5.08 (m,3H), 5.03 (s, 2H), 4.72 (m, 1H), 4.20 (m, 1H), 3.92 (brs, 2H), 3.29(brs, 2H), 3.12 (m, 2H), 2.85 (m, 2H), 1.80-1.30 (m, 8H), 1.00-0.84 (m,12H).

EXAMPLE 15

N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide

To a solution of the compound prepared in example 13 (398 mg) indimethylformamide (4 ml) were added(1S,2R)-benzamidocyclohexanecarboxylic acid (239 mg),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (185 mg),1-hydroxybenzotriazole (148 mg) and N-methylmorpholine (0.46 ml) at 0°C. and the mixture was stirred for 18 hours at room temperature. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with water, a saturated aqueous solution ofsodium bicarbonate and a saturated aqueous solution of sodium chloridesuccessively, dried over anhydrous sodium sulfate and was concentrated.The residue was purified by column chromatography on silica gel(chloroform:methanol=98:2) to give the compound of the present invention(358 mg) having the following physical data.

TLC: Rf 0.69 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.82 and 7.76 (each d, J=6.0 Hz, totally 2H), 7.54 (brd,J=8.2 Hz, 1H), 7.50-7.24 (m, 8H), 6.95 and 6.92 (each d, J=8.4 Hz,totally 1H), 6.80 and 6.77 (each d, J=2.4 Hz, totally 1H), 6.67 and 6.63(each dd, J=8.4, 2.4 Hz, totally 1H), 6.25 and 6.17 (each brd, J=8.1 Hz,totally 1H), 5.01 (s, 2H), 4.69 (m, 1H), 4.31 (m, 1H), 3.92 (m, 2H),3.34 (m, 2H), 3.12 (m, 2H), 2.84 (m, 2H), 2.76 (m, 1H), 2.20-1.20 (m,13H), 0.87, 0.86 and 0.75 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 15(1)-EXAMPLE 15(6)

By the same procedures as described in example 15 using a carboxylicacid corresponding to (1S,2R)-benzamidecyclohexanecarboxylic acid, thecompounds of the present invention having the following physical datawere obtained.

EXAMPLE 15(1)

N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

TLC: Rf 0.61 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.83 and 7.76 (each d, J=7.8 Hz, totally 2H), 7.60-7.25(m, 9H), 6.95 and 6.92 (each d, J=8.4 Hz, totally 1H), 6.80 and 6.77(each d, J=2.4 Hz, totally 1H), 6.67 and 6.63 (each dd, J=8.4, 2.4 Hz,totally 1H), 6.30 and 6.20 (each brd, J=8.4 Hz, totally 1H), 5.02 (s,2H), 4.72 (m, 1H), 4.29 (m, 1H), 3.94 (s, 2H), 3.33 (m, 2H), 3.15 (m,2H), 2.90-2.70 (m, 3H), 2.20-1.20 (m, 13H), 0.87, 0.86 and 0.75 (each d,J=6.3 Hz, totally 6H)

EXAMPLE 15(2)

N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-cyclohexylcarboxamide

TLC: Rf 0.41 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.44-7.30 (m, 5H), 6.97 (d, J=8.4 Hz, 1H), 6.80 (d, J=2.4Hz, 1H), 6.66 (dd, J=8.4, 2.4 Hz, 1H) 5.95 (brd, J=8.4 Hz, 1H), 5.04 (s,2H), 4.73 (m, 1H), 3.93 (s, 2H), 3.37 (d, J=16.8 Hz, 1H), 3.33 (d,J=16.8 Hz, 1H), 3.16 (t, J=5.4 Hz, 2H), 2.86 (t, J=5.4 Hz, 2H), 2.10 (m,1H), 1.90-1.18 (m, 15H), 0.88 (d, J=6.3 Hz, 6H).

EXAMPLE 15(3)

N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]benzamide

TLC: Rf 0.51 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.81 (d, J=7.8 Hz, 2H), 7.56-7.30 (m, 8H), 6.97 (d, J=8.4Hz, 1H), 6.80 (m, 3H), 6.66 (dd, J=8.4, 2.4 Hz, 1H), 5.03 (s, 2H), 5.00(m, 1H), 3.93 (s, 2H), 3.43 (d, J=17.4 Hz, 1H), 3.35 (d, J=17.4 Hz, 1H),3.18 (t, J=5.4 Hz, 2H), 2.86 (t, J=5.4 Hz, 2H), 1.90-1.40 (m, 5H), 0.95(d, J=6.0 Hz, 3H), 0.92 (d, J=6.0 Hz, 3H).

EXAMPLE 15(4)

N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-3-cyclopentylpropanamide

TLC: Rf 0.39 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.48-7.26 (m, 5H), 6.97 (d, J=8.4 Hz, 1H), 6.80 (d, J=2.7Hz, 1H), 6.68 (dd, J=8.4, 2.7 Hz, 1H), 5.96 (brd, J=7.8 Hz, 1H), 5.04(s, 2H), 4.75 (m, 1H), 3.93 (s, 2H), 3.39 (d, J=16.8 Hz, 1H), 3.32 (d,J=16.8 Hz, 1H), 3.17 (t, J=5.4 Hz, 2H), 2.86 (t, J=5.4 Hz, 2H), 2.21 (t,J=7.5 Hz, 2H), 1.84-0.93 (m, 16H), 0.89 (d, J=6.3 Hz, 6H).

EXAMPLE 15(5)

N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-(2-benzyloxyphenyl)carboxamide

TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.21 (brd, J=7.2 Hz, 1H), 8.18 (dd, J=7.5, 1.5 Hz, 1H),7.53-7.23 (m, 11H), 7.10 (m, 2H), 6.96 (d, J=7.8 Hz, 1H), 6.78 (d, J=3.0Hz, 1H), 6.64 (dd, J=7.8, 3.0 Hz, 1H), 5.18 (d, J=10.2 Hz, 1H), 5.12 (d,J=10.2 Hz, 1H), 5.01 (s, 2H), 4.70 (m, 1H), 3.99 (brs, 2H), 3.40 (m,2H), 3.20 (m, 2H), 2.86 (m, 2H), 1.80-1.00 (m, 5H), 0.75 (d, J=6.0 Hz,3H), 0.66 (d, J=6.0 Hz, 3H).

EXAMPLE 15(6)

N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]cinnamide

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.63 (d, J=15.6 Hz, 1H), 7.55-7.30 (m, 10H), 7.00 (d,J=8.1 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 6.70 (dd, J=8.1, 2.7 Hz, 1H),6.43 (d, J=15.6 Hz, 1H), 6.34 (brd, J=7.5 Hz, 1H), 5.03 (s, 2H), 4.92(m, 1H), 3.97 (brs, 2H), 3.43 (d, J=17.4 Hz, 1H), 3.34 (d, J=17.4 Hz,1H), 3.19 (m, 2H), 2.85 (m, 2H), 1.84-1.40 (m, 5H), 1.00-0.93 (m, 6H)

EXAMPLE 16

1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone

To a solution of the compound prepared in Example 12 (1.41 g) inethanol(26 ml) was added 10% palladium-carbon (140 mg) and the mixturewas stirred for 6 hours under atmosphere of hydrogen. The reactionmixture was filtered and the filtrate was concentrated. The residue waspurified by column chromatography on silica gel(chloroform:methanol=97:3) to give the compound of the present invention(275 mg) having the following physical data.

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 6.89 (d, J=8.1 Hz, 1H), 6.63 (d, J=2.7 Hz, 1H), 6.53 (dd,J=8.1, 2.7 Hz, 1H), 5.00 (brd, J=7.4 Hz, 1H), 4.40 (m, 1H), 3.90 (s,2H), 3.31 (s, 2H), 3.14 (m, 2H), 2.83 (m, 2H), 1.70 (m, 2H), 1.60-1.20(m, 12H), 0.90 (d, J=6.6 Hz, 6H)

EXAMPLE 17

1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-amino-5-methyl-2-hexanonedihydrochloride

By the same procedure as described in example 2 using the compoundprepared in example 16 in place of the compound prepared in example 1,the compound of the present invention having the following physical datawas obtained.

NMR (DMSO-d₆): δ 9.80 (m, 1H), 8.62 (m, 2H), 7.10 (m, 1H), 6.70 (d,J=2.4 Hz, 1H), 6.63 (brd, J=8.4 Hz, 1H), 4.60-4.10 (m, 5H), 3.40 (m,2H), 2.90 (m, 2H), 2.00-1.42 (m, 5H), 1.00-0.80 (m, 6H)

EXAMPLE 18

(2S)-N-[1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

To a solution of the compound prepared in example 17 (120 mg) indimethylformamide (2 ml) were added(2S)-2-benzyloxycarbonylamino-4-methylpentanoic acid (95 mg),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (69 mg),1-hydroxybenzotriazole (55 mg) and N-methylmorpholine (0.084 ml) at 0°C. and the mixture was stirred for 18 hours at room temperature. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with water, a saturated aqueous solution ofsodium bicarbonate and a saturated aqueous solution of sodium chloridesuccessively, dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=1:1) to give the compound (89 mg) ofthe present invention having the following physical data.

TLC: Rf 0.65 (ethyl acetate);

NMR (CDCl₃): δ 7.34 (m, 5H), 6.88 (m, 1H), 6.63 (m, 1H), 6.51 (m, 1H),6.58 and 6.40 (each brd, J=7.8 Hz, totally 1H), 5.20-5.08 (m, 3H), 4.72(m, 1H), 4.20 (m, 1H), 3.86 (s, 2H), 3.28 (m, 2H), 3.11 (m, 2H), 2.82(m, 2H), 1.90-1.20 (m, 8H), 1.00-0.84 (m, 12H).

EXAMPLE 18(1)

N-[1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

By the same procedure as described in example 18 using(−)-2-benzamidocyclohexanecarboxylic acid((1R,2S)-2-benzamidecyclohexanecarboxylic acid) in place of(2S)-2-benzyloxycarbonylamino-4-methylpentanoic acid, the compound ofthe present invention having the following physical data was obtained.

TLC: Rf 0.33 (ethyl acetate);

NMR (CDCl₃): δ 7.88-7.70 (m, 2H), 7.62-7.30 (m, 4H), 6.86 and 6.80 (eachd, J=8.4 Hz, totally 1H), 6.64 and 6.57 (each d, J=2.7 Hz, totally 1H),6.51 and 6.47 (each dd, J=8.4, 2.7 Hz, totally 1H), 6.17 and 6.09 (eachbrd, J=8.4 Hz, totally 1H), 4.68 (m, 1H), 4.28 (m, 1H), 3.91 and 3.86(each s, totally 2H), 3.32-3.25 (m, 2H), 3.13 (m, 2H), 2.90-2.60 (m,3H), 2.20-1.20 (m, 13H), 0.88 and 0.75 (each d, J=6.3 Hz, totally 6H).

REFERENCE EXAMPLE 8

4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

By the same procedure as described in reference example 2 using2,3,4,5-tetrahydro-1H-1,4-benzodiazepine in place of(1R,2S)-2-aminocyclohexylmethylalcohol, the title compound having thefollowing physical data was obtained.

TLC: Rf 0.70 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.21-7.10 (m, 2H), 7.12 (t, J=6.8 Hz, 1H), 6.79 (d, J=6.8Hz, 1H), 4.43-4.35 (m, 2H), 3.65 (m, 2H), 3.15 (m, 2H), 1.53 and 1.41(each s, totally 9H).

REFERENCE EXAMPLE 9

1-benzyl-4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

Under atmosphere of argon, to a solution of the compound prepared inreference example 8 (276 mg) in dimethylformamide (3.0 ml) was addedpotassium carbonate (336 mg) and the mixture was stirred for 30 minutesat room temperature, then thereto was added benzyl bromide (0.30 ml) andthe mixture was stirred for another 30 hours. To the reaction mixturewas added water and was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous solution of sodium bicarbonate and asaturated aqueous solution of sodium chloride successively, dried overanhydrous magnesium sulfate and was concentrated. The residue waspurified by column chromatography on silica gel (n-hexane:ethylacetate=9:1) to give the title compound (366 mg) having the followingphysical data.

TLC: Rf 0.60 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.43-7.19 (m, 8H), 7.00 (d, J=8.7 Hz, 1H), 6.93 (t, J=8.7Hz, 1H), 4.55 (m, 2H), 4.37 (s, 2H), 3.48 (m, 2H), 3.00 (m, 2H), 1.42(s, 9H, Boc).

REFERENCE EXAMPLE 10

1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine dihydrochloride

By the same procedure as described in example 2 using the compoundprepared in reference example 9 in place of the compound described inexample 1, the title compound having the following physical data wasobtained.

TLC: Rf 0.23 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 9.35 (m, 1H), 7.43-7.20 (m, 7H), 7.07 (d, J=8.1 Hz,1H), 6.95 (t, J=7.5 Hz, 1H), 4.41 (m, 2H), 4.24 (m, 2H), 3.20-3.02 (m,4H).

EXAMPLE 19

(3S)-3-amino-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-heptanonetrihydrochloride

By the same procedure as described in example 1->example 2 using thecompound prepared in reference example 10 in place of1,3,4,5-tetrahydro-2-benzazepine, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.65 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.70 (m, 2H), 7.50-7.21 (m, 7H), 7.06 (d, J=8.1 Hz,1H), 6.98 (t, J=7.5 Hz, 1H), 4.80-4.20 (m, 5H), 3.40 (m, 6H), 1.90-1.50(m, 3H), 1.00-0.90 (m, 6H).

EXAMPLE 20

(2S)-N-[(3S)-5-methyl-2-oxo-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

By the same procedure as described in example 14 using the compoundprepared in reference example 10 in place of the compound prepared inreference example 7, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.30 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.43-6.82 (m, 14H), 6.39 (brd, J=8.4 Hz, 1H), 5.20-5.05(m, 3H), 4.78 (m, 1H), 4.34 (s, 2H), 4.19 (m, 1H), 3.95 (s, 2H), 3.35(s, 2H), 3.00-2.72 (m, 4H), 1.80-1.21 (m, 6H), 1.00-0.82 (m, 12H).

EXAMPLE 21-EXAMPLE 21(3)

By the same procedure as described in example 3 using the compoundprepared in example 19 in place of the compound prepared in example 2,and a carboxylic acid corresponding to(−)-2-benzamidecyclohexanecarboxylic acid((1R,2S)-2-benzamidecyclohexanecarboxylic acid), the compounds of thepresent invention having the following physical data were obtained.

EXAMPLE 21

N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-1-cyclohexylcarboxamide

TLC: Rf 0.68 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.43-7.18 (m, 6H), 7.15 (d, J=7.5 Hz, 1H), 7.01 (d, J=7.8Hz, 1H), 6.91 (t, J=7.5 Hz, 1H), 5.93 (brd, J=8.4 Hz, 1H), 4.79 (m, 1H),4.34 (s, 2H), 3.97 (s, 2H), 3.43 (d, J=17.2 Hz, 1H), 3.39 (d, J=17.2 Hz,1H), 3.00-2.80 (m, 4H), 2.12 (m, 1H), 1.90-1.20 (m, 13H), 0.90 (d, J=6.3Hz, 6H)

EXAMPLE 21(1)

N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-3-cyclopentylpropanamide

TLC: Rf 0.72 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.42-7.20 (m, 6H), 7.16 (d, J=8.1 Hz, 1H), 7.03 (d, J=7.8Hz, 1H), 6.93 (t, J=8.1 Hz, 1H), 5.99 (brd, J=8.7 Hz, 1H), 4.80 (m, 1H),4.34 (s, 2H), 4.00 (s, 2H), 3.48 (d, J=17.4 Hz, 1H), 3.41 (d, J=17.4 Hz,1H), 3.00-2.80 (m, 4H), 2.21 (t, J=7.5 Hz, 2H), 1.84-0.92 (m, 14H), 0.90(d, J=6.3 Hz, 6H).

EXAMPLE 21(2)

N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

TLC: Rf 0.33 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.80 (m, 2H), 7.75-7.05 (m, 1H), 7.01 (d, J=7.8 Hz, 1H),6.93 (t, J=8.1 Hz, 1H), 6.20 (brd, J=8.0 Hz, 1H), 4.79 (m, 1H), 4.35 (s,2H), 4.31 (m, 1H), 3.99 (s, 2H), 3.40 (s, 2H), 3.00-2.65 (m, 5H),2.20-1.20 (m, 11H), 1.00-0.70 (m, 6H).

EXAMPLE 21(3)

N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxybenzamide

TLC: Rf 0.70 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.21 (m, 2H), 7.60-7.02 (m, 15H), 6.99 (d, J=8.1 Hz, 1H),6.88 (t, J=7.5 Hz, 1H), 5.17 (d, J=10.5 Hz, 1H) 5.12 (d, J=10.5 Hz, 1H),4.79 (m, 1H), 4.33 (s, 2H), 3.92 (s, 2H), 3.43 (d, J=17.7 Hz, 1H), 3.36(d, J=17.7 Hz, 1H), 2.98-2.73 (m, 4H), 1.40-0.82 (m, 3H), 0.76 (d, J=6.0Hz, 3H), 0.66 (d, J=6.0 Hz, 3H).

REFERENCE EXAMPLE 11

ethyl2-(4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)acetate

To a solution of the compound prepared in reference example 8 (2.48 g)in dimethylformamide (1 ml) were added a suspension of sodium hydride(0.6 g) in dimethylformamide (1 ml) and bromoethyl acetate(1.66 ml) at0° C. and the mixture was stirred for 2.5 hours at 80° C. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with water and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous magnesium sulfateand was concentrated. The residue was purified by column chromatographyon silica gel (n-hexane:ethyl acetate 9:9:1) to give the compound of thepresent invention (1.38 g) having the following physical data.

TLC: Rf 0.68 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.18 (m, 2H), 6.91 (dd, J=7.2, 0.9 Hz, 1H), 6.79 (m, 1H),4.40 (m, 2H), 4.23 (q, J=6.9 Hz, 2H), 4.01 (s, 2H), 3.64 (m, 2H),. 3.20(m, 2H), 1.41 (s, 9H), 1.30 (t, J=6.9 Hz, 3H).

REFERENCE EXAMPLE 12

2-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)acetic acid ethyl esterdihydrochloride

By the same procedure as described in example 2 using the compoundprepared in reference example 11 in place of the compound prepared inexample 1, the title compound having the following physical data wasobtained.

TLC: Rf 0.01 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 9.20 (br, 1H), 7.32 (dd, J=7.5, 1.5 Hz, 1H), 7.27 (dt,J=1.5, 7.5 Hz, 1H), 6.93 (dt, J=0.6, 7.2 Hz, 1H), 6.81 (d, J=8.4 Hz,1H), 4.22-4.03 (m, 6H), 3.42-3.18 (m, 4H), 1.21 (m, 3H).

EXAMPLE 22

(2S)-N-[(3S)-1-(1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in example 14 using the compoundprepared in reference example 12 in place of the compound prepared inreference example 7, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.33 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.34 (s, 5H), 7.26 (t, J=7.8 Hz, 1H), 7.07 (d, J=7.8 Hz,1H), 6.88 (t, J=7.8 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.42 (brd, J=8.4Hz, 1H), 5.13 (m, 3H), 4.78 (m, 1H), 4.23 (q, J=6.9 Hz, 2H), 4.20 (m,1H), 3.99 (s, 2H), 3.90 (s, 2H), 3.41 (m, 2H), 3.20 (m, 2H), 3.00 (m,2H), 1.80-1.30 (m, 6H), 1.28 (t, J=6.9 Hz, 3H), 1.00-0.84 (m, 12H)

EXAMPLE 22(1)-EXAMPLE 22(4)

By the same procedure as described in reference example 11->referenceexample 12->example 22 using a halogen compound corresponding tobromoacetic acid, the compound of the present invention having thefollowing physical data was obtained.

EXAMPLE 22(1)

(2S)-N-[(3S)-5-methyl-1-(1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.24 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40-6.80 (m, 9H), 6.40 (brd, J=8.2 Hz, 1H), 5.20-5.08(m, 3H), 4.75 (m, 1H), 4.20 (m, 1H), 3.86 (s, 2H), 3.37 (s, 2H), 2.97(s, 4H), 2.89 (s, 3H), 1.80-1.21 (m, 6H), 1.00-0.82 (m, 12H).

EXAMPLE 22(2)

(2S)-N-[(3S)-5-methyl-2-oxo-1-(1-(3-phenylpropyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.65 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40-7.04 (m, 12H), 6.88 (m, 2H), 6.60 and 6.44 (eachbrd, J=7.8 Hz, totally 1H), 5.20-5.06 (m, 3H), 4.79 (m, 1H), 4.20 (m,1H), 3.85 (s, 2H), 3.36 (s, 2H), 3.18 (t, J=6.9 Hz, 2H), 2.95 (m, 4H),2.70 (t, J=6.9 Hz, 2H), 1.90 (quintet, J=6.9 Hz, 2H), 1.80-1.30 (m, 6H),1.00-0.82 (m, 12H)

EXAMPLE 22(3)

(2S)-N-[(3S)-5-methyl-2-oxo-1-(1-phenethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.71 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40-6.80 (m, 14H), 7.08 (d, J=7.5 Hz, 1H), 6.98 (d,J=7.5 Hz, 1H), 6.87 (d, J=7.5 Hz, 1H), 6.38 (m, 1H), 5.12 (m, 3H), 4.75(m, 1H), 4.20 (m, 1H), 3.80 (s, 2H), 3.44 (t, J=6.9 Hz, 2H), 3.35 (s,2H), 3.04 (m, 2H), 2.88 (m, 4H), 1.75-1.30 (m, 6H), 1.00-0.82 (m, 12H).

EXAMPLE 22(4)

(2S)-N-[(3S)-5-methyl-1-(1-isopropyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.53 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.34 (s, 5H), 7.20 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.5 Hz,1H), 6.97 (d, J=7.5 Hz, 1H), 6.82 (t, J=7.5 Hz, 2H), 6.40 (brd, J=8.1Hz, 1H), 5.20-5.08 (m, 3H), 4.79 (m, 1H), 4.20 (m, 1H), 3.80 (m, 3H),3.40 (s, 2H), 2.98 (m, 2H), 2.88 (m, 2H), 1.76-1.34 (m, 6H), 1.22 (d,J=6.6 Hz, 6H), 1.00-0.85 (m, 12H).

EXAMPLE 23

(2S)-N-[5-methyl-1-(1-carboxymethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

To a solution of the compound prepared in example 22 (550 mg) intetrahydrofuran (3 ml)-methanol (3 ml) was added 1N aqueous solution ofsodium hydroxide (1 ml) and the mixture was stirred for 2 hours at roomtemperature. The reaction mixture was neutralized by adding 1Nhydrochloric acid and was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and was concentrated. The residuewas washed with a mixture of hexane-ethyl acetate to give the compoundof the present invention (522 mg) having the following physical data.

TLC: Rf 0.50 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 8.25 and 8.13 (each brd, J=7.5 Hz, totally 1H), 7.40(brd, J=7.8 Hz, 1H), 7.33 (s, 5H), 7.09 (t, J=7.3 Hz, 1H), 7.02 (d,J=7.3 Hz, 1H), 6.75 (t, J=7.3 Hz, 1H), 6.69 (d, J=7.3 Hz, 1H), 5.00 (s,2H), 4.45-4.30 (m, 1H), 4.04 (m, 1H), 3.90 (brs, 2H), 3.69 (brs, 2H),3.40 (m, 2H), 3.10 (m, 2H), 2.80 (m, 2H), 1.70-1.30 (m, 6H), 0.92-0.70(m, 12H)

EXAMPLE 24

(2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in example 14 using2,3,4,5-tetrahydro-1H-1,4-benzodiazepine in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data.

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.34 (s, 5H), 7.10 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.8 Hz,1H), 6.83 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.42 (brd, J=8.4Hz, 1H), 5.11 (m, 3H), 4.75 (m, 1H), 4.19 (m, 1H), 3.89 (s, 2H), 3.43(s, 2H), 3.16-3.00 (m, 4H), 1.78-1.32 (m, 6H), 1.00-0.82 (m, 12H).

REFERENCE EXAMPLE 13

2-(4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)aceticacid

By the same procedure as described in example 23 using the compoundprepared in reference example 11 in place of the compound prepared inexample 22, the compound of the present invention having the followingphysical data.

TLC: Rf 0.18 (ethyl acetate);

NMR (DMSO-d₆): δ 7.10 (m, 2H), 6.82 (m, 1H), 6.65 (m, 1H), 4.38 (m, 2H),3.96 (m, 2H), 3.56 (m, 2H), 3.22 (m, 2H), 1.45-1.23 (m, 9H).

REFERENCE EXAMPLE 14

2-(4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)acetamide

To a solution of the compound prepared in reference example 13 (400 mg)in dimethylformamide (5 ml) were added ammonium carbonate (308 mg) and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (353 mg) and the mixturewas stirred for 2 hours at 80° C. To the reaction mixture was added asaturated aqueous solution of sodium bicarbonate and was extracted withethyl acetate. The organic layer was washed with water, a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous magnesium sulfateand was concentrated. The residue was purified by column chromatographyon silica gel (n-hexane:ethyl acetate=1:1) to give the compound of thepresent invention (285 mg) having the following physical data.

TLC: Rf 0.32 (ethyl acetate);

NMR (CDCl₃): δ 7.40-6.85 (m, 4H), 6.62 and 5.43 (each m, totally 2H),4.51 (m, 2H), 3.89 (s, 2H), 1.43 (m, 9H).

REFERENCE EXAMPLE 15

2-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)acetamidedihydrochloride

By the same procedure as described in example 2 using the compoundprepared in reference example 14 in place of the compound prepared inexample 1, a crude product having the following physical data of thetitle compound was given. The crude product was used in the nextreaction without further purification.

TLC: Rf 0.01 (chloroform:methanol:acetic acid=9:1:1).

EXAMPLE 25

(2S)-N-[(3S)-1-(1-aminocarbonylmethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in example 14 using the compoundprepared in reference example 15 in place of the compound prepared inreference example 7, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.33 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.34 (m, 5H), 7.21 (t, J=6.9 Hz, 1H), 7.10 (d, J=6.9 Hz,1H), 7.04-6.88 (m, 3H), 6.51 (brd, J=7.5 Hz, 1H), 5.68 (brs, 1H), 5.20(brd, J=7.2 Hz, 1H), 5.10 (s, 2H), 4.70 (m, 1H), 4.21 (m, 1H), 3.93(brs, 2H), 3.90 (s, 2H), 3.50 (d, J=13.2 Hz, 1H), 3.40 (d, J=13.2 Hz,1H), 3.20-2.90 (m, 4H), 1.80-1.38 (m, 6H), 1.05-0.87 (m, 12H).

REFERENCE EXAMPLE 16

4-(t-butoxycarbonyl)-1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

To a solution of the compound prepared in reference example 11 (200 mg)in tetrahydrofuran (3 ml) was added a suspension of lithium aluminumhydride (34 mg) in tetrahydrofuran at 0° C. and the mixture was stirredfor 2 hours at room temperature. To the reaction mixture was addedice-water and 15% aqueous solution of sodium hydroxide and the mixturewas filtered. The filtrate was concentrated and the residue was driedunder reduced pressure to give the title compound having the followingphysical data as a crude product. The crude product was used in the nextreaction without further purification.

TLC: Rf 0.22 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.20 (m, 2H), 6.92 (m, 2H), 4.42 (brs, 2H), 3.80-3.60 (m,4H), 3.43 (m, 2H), 3.30-3.10 (m, 2H), 1.35 (s, 9H).

REFERENCE EXAMPLE 17

1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinedihydrochloride

By the same procedure as described in example 2 using the compoundprepared in reference example 16 in place of the compound prepared inexample 1, a crude product of the title compound was obtained. The crudeproduct was used in the next reaction without further purification.

EXAMPLE 26

(2S)-N-[1-(1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in example 14 using the compoundprepared in reference example 17 in place of the compound prepared inreference example 7, and(2S)-N-[1-bromo-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamidein place of(2S)-N-[(3S)-1-bromo-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,the compound of the present invention having the following physical datawas obtained.

TLC: Rf 0.48 (ethyl acetate);

NMR (CDCl₃): δ 7.40-6.82 (m, 9H), 6.77 and 6.44 (each brd, J=7.8 Hz,totally 1H), 5.20-5.08 (m, 3H), 4.70 (m, 1H), 4.20 (m, 1H), 3.87 (m,2H), 3.71 (t, J=5.4 Hz, 2H), 3.41 (m, 4H), 3.05 (m, 2H), 2.97 (m, 2H),1.90-1.30 (m, 6H), 1.00-0.82 (m, 12H).

REFERENCE EXAMPLE 18

4-(t-butoxycarbonyl)-1-cyanomethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

To a solution of the compound prepared in reference example 14 (101 mg)in methylene chloride (2 ml) were added pyridine (60 μl) and tosylchloride(138 mg) at 0° C. and the mixture was stirred for 2 hours at 80°C. To the reaction mixture was added water and was extracted with ethylacetate. The organic layer was washed with water, a saturated aqueoussolution of sodium bicarbonate and a saturated aqueous solution ofsodium chloride successively, and dried over anhydrous magnesiumsulfate. The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=7:3) to give the compound (33 mg) having thefollowing physical data.

TLC: Rf 0.88 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.40-7.20 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 7.04 (t, J=8.1Hz, 1H), 4.42-4.30 (m, 2H), 4.11 (s, 2H), 3.63 (br, 2H), 3.15 (m, 2H),1.42 (s, 9H).

EXAMPLE 27

(2S)-N-[(3S)-1-(1-cyanomethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in example 2->example 14 using thecompound prepared in reference example 18 in place of the compoundprepared in example 1, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40-7.25 (m, 6H), 7.13 (d, J=6.6 Hz, 1H), 7.05 (d, J=6.6Hz, 1H), 7.00 (t, J=6.6 Hz, 1H), 6.35 (brd, J=7.5 Hz, 1H), 5.10 (m, 3H),4.75 (m, 1H), 4.19 (m, 1H), 4.08 (s, 2H), 3.87 (s, 2H), 3.36 (m, 2H),3.18-3.00 (m, 4H), 1.80-1.38 (m, 6H), 1.00-0.88 (m, 12H).

REFERENCE EXAMPLE 19-A-REFERENCE EXAMPLE 19-B

To a solution of 4-chromanone (5.00 g) in chloroform (60 ml) were addedunder cooling with ice conc. sulfic acid (25 ml) and sodium azide (4.42g) over a period of 30 minutes and the mixture was stirred for 2 hoursat room temperature. The reaction mixture was poured into ice-water andthe mixture was alkalified with potassium carbonate and was extractedwith methylene chloride. The organic layer was washed with water, asaturated aqueous solution of sodium bicarbonate and a saturated aqueoussolution of sodium chloride successively, dried over anhydrous magnesiumsulfate and was concentrated. The residue was purified by columnchromatography on silica gel (toluene:ethyl acetate=1:1) to give thecompound of reference example 19-A (3.1 g) and the compound of referenceexample 19-B (100 mg) having the following physical data.

REFERENCE EXAMPLE 19-A

2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one

TLC: Rf 0.45 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.60 (m, 1H), 7.10-6.87 (m, 4H), 4.47 (t, J=6.0 Hz, 2H),2.86 (t, J=6.0 Hz, 2H).

REFERENCE EXAMPLE 19-B

2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.97 (dd, J=11.1, 1.5 Hz, 1H), 7.44 (dt, J=1.5, 8.1 Hz,1H), 7.37 (m, 1H), 7.14 (dt, J=1.2, 8.1 Hz, 1H), 7.02 (dd, J=1.2, 8.1Hz, 1H), 4.40 (t, J=4.8 Hz, 2H), 3.51 (q, J=4.8 Hz, 2H).

REFERENCE EXAMPLE 20-A

2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride

To a solution of the compound prepared in reference example 19-A (3.05g) in tetrahydrofuran (30 ml) was added a suspension of lithium aluminumhydride (2.5 g) in tetrahydrofuran (80 ml) and the mixture was refluxedfor 24 hours. To the reaction mixture were added ice-water and 15%aqueous solution of sodium hydroxide and the mixture was filtered. Tothe filtrate was added water and the mixture was extracted withmethylene chloride. The organic layer was washed with water and asaturated aqueous solution of sodium chloride successively, dried overanhydrous magnesium sulfate and was concentrated. The residue wasdissolved in ethyl acetate (20 ml) and thereto was added 4N hydrochloricacid-ethyl acetate (40 ml) under cooling with ice, and the mixture wasstirred for 30 minutes at room temperature. The reaction mixture wasconcentrated. The residue was washed with diethyl ether-ethyl acetate(7:3) to give the title compound (3.30 g) having the following physicaldata.

TLC: Rf 0.71 (chloroform:methanol:water=6:4:1);

NMR (DMSO-d₆): δ 9.72 (m, 2H), 7.47-7.27 (m, 2H), 7.20-7.01 (m, 4H).3.50 (m, 2H).

REFERENCE EXAMPLE 20-B

2,3,4,5-tetrahydro-1,5-benzoxazepine

To a solution of the compound prepared in reference example 19-B (95 mg)in tetrahydrofuran (1 ml) was added a suspension of lithium aluminumhydride (77 mg) in tetrahydrofuran (1 ml) at 0° C. and the mixture wasrefluxed for 2 hours. To the reaction mixture was added ice-water and15% aqueous solution of sodium hydroxide and was filtered. The filtratedwas extracted with methylene chloride. The organic layer was washed withwater and a saturated aqueous solution of sodium chloride successively,dried over anhydrous sodium sulfate and was concentrated. The residuewas purified by column chromatography on silica gel (toluene:ethylacetate=1:1) to give the title compound (45 mg) having the followingphysical data.

TLC: Rf (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 6.96 (dd, J=7.8, 1.5 Hz, 1H), 6.87 (dt, J=1.5, 7.8 Hz,1H), 6.78 (dt, J=1.8, 7.8 Hz, 1H), 6.72 (dd, J=7.8, 1.8 Hz, 1H), 6.72(dd, J=7.8, 1.8 Hz, 1H), 4.40 (t, J=4.8 Hz, 2H), 3.51 (q, J=4.8 Hz, 2H).

EXAMPLE 28

(2S)-N-[(3S)-1-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in example 14 using the compoundprepared in reference example 20-A in place of the compound prepared inreference example 7, the compound of the present invention having thefollowing physical data.

TLC: Rf 0.45 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40-6.95 (m, 9H), 6.34 (brd, J=7.5 Hz, 1H), 5.10 (brs,3H), 4.75 (m, 1H), 4.20 (m, 1H), 4.06 (m, 2H), 3.94 (d, J=14.7 Hz, 1H),3.88 (d, J=14.7 Hz, 1H), 3.44 (s, 2H), 3.14 (m, 2H), 1.80-1.30 (m, 6H),1.00-0.84 (m, 12H).

EXAMPLE 29

(2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,5-benzoxazepin-5-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in Example 14, using the compoundprepared in Reference Example 20-B in place of the compound prepared inreference example 7, the compound of the present invention was obtained.

TLC: Rf 0.53 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.34 (s, 5H), 6.98-6.58 (m, 4H), 6.42 (brd, J=6.6 Hz,1H), 5.10 (m, 3H); 4.78 (m, 1H), 4.23-4.05 (m, 5H), 3.38-3.19 (m, 2H),2.18-1.98 (m, 2H), 1.74-1.40 (m, 6H), 1.00-0.84 (m, 12H).

EXAMPLE 30

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

By the same procedure as described in example 1->example 2->example 3using the compound prepared in reference example 20-A in place of1,3,4,5-tetrahydro-2-benzazepine, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.77 (dd, J=8.0, 1.8 Hz, 2H), 7.50-7.38 (m, 3H),7.30-6.95 (m, 5H), 6.15 (brd, J=8.0 Hz, 1H), 4.81-4.70 (m, 1H),4.40-4.22 (m, 1H), 4.10-4.00 (m, 2H), 3.91 (d, J=14.8 Hz, 1H), 3.88 (d,J=14.8 Hz, 1H), 3.45 (s, 2H), 3.20-3.10 (m, 2H), 2.82-2.71 (m, 1H),2.20-1.20 (m, 11H), 0.76 (d, J=6.2 Hz, 3H), 0.74 (d, J=6.2 Hz, 3H)

REFERENCE EXAMPLE 21

2,3,4,5-tetrahydro-1,4-benzothiazepin-5-one

By the same procedure as described in reference example 5 using3,4-dihydro-2H-1-benzothiin-4-one in place of 6-hydroxy-1-tetralone, thetitle compound having the following physical data was obtained as acrude product. The crude product was used in the next reaction withoutfurther purification.

TLC: Rf 0.44 (chloroform:methanol=9:1).

REFERENCE EXAMPLE 22

2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride

To a solution of the compound prepared in reference example 21 (820 mg)in tetrahydrofuran (10 ml) was added boron hydride (1M tetrahydrofuransolution, 11.5 ml) and the mixture was stirred for 3 hours. To thereaction mixture was added methanol and was concentrated. To the residuewas added 6N hydrochloric acid and was refluxed for 3 hours. Thereaction mixture was concentrated to give the title compound having thefollowing physical data as a crude product.

TLC: Rf 0.48 (chloroform:methanol:acetic acid=9:1:1);

NMR (DMSO-d₆): δ 9.61 (m, 1H), 7.58 (m, 2H), 7.37 (m, 2H), 4.39 (brs,2H), 3.42 (m, 2H), 3.05 (m, 2H).

EXAMPLE 31

(2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in example 14 using the compoundprepared in reference example 22 in place of the compound prepared inreference example 7, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.18 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.55 (m, 1H), 7.35 (s, 5H), 7.15 (m, 3H), 6.38 (brd,J=7.8 Hz, 1H), 5.11 (m, 3H), 4.72 (m, 1H), 4.20 (m, 3H), 3.38 (m, 4H),2.78 (m, 2H), 1.80-1.35 (m, 6H), 1.05-0.87 (m, 12H).

EXAMPLE 31(1)

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

By the same procedure as described in example 1->example 2->example 3using the compound prepared in reference example 22 in place of1,3,4,5-tetrahydro-2-benzazepine, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.54 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.76 (m, 2H), 7.60-7.32 (m, 4H), 7.30-7.10 (m, 4H), 6.10(brd, J=8.4 Hz, 1H), 4.75 (m, 1H), 4.30 (m, 1H), 4.21 (s, 2H), 3.38 (m,4H), 2.79 (m, 3H), 2.10-1.21 (m, 11H), 0.80 (d, J=6.2 Hz, 6H).

REFERENCE EXAMPLE 23

4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine

By the same procedure as described in reference example 2 using thecompound prepared in reference example 22 in place of(1R,2S)-2-aminocyclohexylmethylalcohol, the title compound having thefollowing physical data was obtained.

TLC: Rf 0.53 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.60-7.12 (m, 4H), 4.58 (m, 2H), 3.92 (m, 2H), 2.81 (m,2H), 1.45 (m, 9H).

REFERENCE EXAMPLE 24

4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide

To a solution of the compound prepared in reference example 23 (140 mg)in methylene chloride (4 ml) was added 3-chloroperbenzoic acid (400 mg)and the mixture was stirred for 2 hours at room temperature. Thereaction mixture was concentrated, and to the residue was added ethylacetate, and the organic layer was washed with water, a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride successively, and was dried. The residue was purifiedby column chromatography on silica gel (n-hexane:ethyl acetate=3:1) togive the title compound (190 mg) having the following physical data.

TLC: Rf 0.27 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 8.09 (m, 1H), 7.61-7.35 (m, 3H), 4.73 (s, 2H), 4.10 (m,2H), 3.35 (m, 2H), 1.38 (s, 9H).

REFERENCE EXAMPLE 25

2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide hydrochloride

By the same procedure as described in example 2 using the compoundprepared in reference example 24 in place of the compound prepared inexample 1, the title compound having the following physical data wasobtained.

TLC: Rf 0.57 (chloroform:methanol:ethyl acetate=9:1:1);

NMR (DMSO-d₆): δ 9.79 (m, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.85-7.67 (m,3H), 4.58 (s, 2H), 3.83 (m, 2H), 3.70 (m, 2H).

EXAMPLE 32

(2S)-N-[(3S)-5-methyl-2-oxo-1-(1,1-dioxo-2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in example 14 using the compoundprepared in reference example 25 in place of the compound prepared inreference example 7, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.36 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.08 (dd, J=7.4, 1.8 Hz, 1H), 7.60-7.42 (m, 2H), 7.34 (s,5H), 7.23 (m, 1H), 6.35 (brd, J=7.8 Hz, 1H), 5.15-5.00 (m, 3H), 4.62 (m,1H), 4.39 (brs, 2H), 4.19 (m, 1H), 3.60 (m, 2H), 3.38 (m, 4H), 1.80-1.38(m, 6H), 1.01-0.84 (m, 12H).

EXAMPLE 32(1)

N-[(3S)-5-methyl-2-oxo-1-(1,1-dioxo-2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

By the same procedure as described in example 1->example 2->example 3using the compound prepared in reference example 25 in place of1,3,4,5-tetrahydro-2-benzazepine, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.39 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.08 (dd, J=7.2, 2.1 Hz, 1H), 7.75 (m, 2H), 7.55-7.40 (m,5H), 7.24 (m, 1H), 7.11 (brd, J=8.4 Hz, 1H), 6.05 (brd, J=8.1 Hz, 1H),4.63 (q, J=8.1 Hz, 1H), 4.50-4.30 (m, 3H), 3.60 (m, 2H), 3.41-3.22 (m,4H), 2.80 (q, J=5.1 Hz, 1H), 2.10-1.21 (m, 11H), 0.83-0.74 (m, 6H).

REFERENCE EXAMPLE 26

1,2,4,5-tetrahydro-3,2-benzothiazepine-3,3-dioxide

To a solution of 2-phenylethanesulfonamide (3.62 g) in methanesulfonicacid (20 ml)-acetic acid (5 ml) was added a solution of trioxane (582mg) in trifluoroacetic acid (3 ml)and the mixture was stirred for 3hours at 35° C. To the reaction mixture was added water and wasextracted with chloroform. The organic layer was washed with water and asaturated aqueous solution of sodium bicarbonate, dried over anhydroussodium sulfate and was concentrated. The residue was purified by columnchromatography on silica gel (chloroform:methanol=100:1) to give thetitle compound (1.78 g) having the following physical data.

TLC: Rf 0.55 (chloroform:methanol=100:1);

NMR (CDCl₃): δ 7.40-7.20 (m, 4H), 4.42-4.20 (br, 3H), 3.20-3.05 (br,4H).

EXAMPLE 33

(2S)-N-[(3S)-5-methyl-2-oxo-1-(3,3-dioxo-1,2,4,5-tetrahydro-3,2-benzothiazepin-2-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in example 14 using the compoundprepared in reference example 26 in place of the compound prepared inreference example 7, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.70 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.42-7.13 (m, 9H), 6.33 (brd, J=6.9 Hz, 1H), 5.11 (s,2H), 5.10 (m, 1H), 4.82-4.30 (br, 3H), 4.19 (m, 1H), 4.03-3.70 (br, 2H),3.40-3.00 (m, 4H), 1.80-1.30 (m, 6H), 1.05-0.83 (m, 12H).

EXAMPLE 33(1)

N-[(3S)-5-methyl-2-oxo-1-(3,3-dioxo-1,2,4,5-tetrahydro-3,2-benzothiazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

By the same procedure as described in example 1->example 2->example 3using the compound prepraed in reference example 26 in place of1,3,4,5-tetrahydro-2-benzazepine, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.42 (n-hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 8.12 (d, J=7.2 Hz, 1H), 7.83-7.70 (m, 3H), 7.57-7.10(m, 7H), 4.60-4.12 (m, 4H), 3.90-3.50 (m, 2H), 3.40-3.07 (m, 4H), 2.72(m, 1H), 2.11-1.08 (m, 11H), 0.67 (d, J=6.2 Hz, 3H), 0.53 (d, J=6.2 Hz,3H).

REFERENCE EXAMPLE 27

2-(2,2-dimethoxyethylaminosulfonyl)nitrobenzene

To a solution of 2,2-dimethoxyethylamine (2.61 g) in methylene chloride(100 ml) were added 2-nitrophenylsulfonylchloride (5.0 g) anddiisopropylethylamine (5 ml) dropwise at −78° C. and the mixture wasstirred for 10 minutes at room temperature. To the reaction mixture wasadded 1N hydrochloric acid and was extracted with chloroform. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and was concentrated togive the title compound having the following physical data.

TLC: Rf 0.56 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.20-8.10 (m, 1H), 7.92-7.88 (m, 1H), 7.82-7.70 (m, 2H),5.65-5.50 (m, 1H), 4.37 (t, J=5.6 Hz, 1H), 3.32 (s, 6H), 3.23 and 3.20(each d, J=5.4 Hz, each 1H).

REFERENCE EXAMPLE 28

2H,3H,4H,5H-benzo[f]-1,2,5-thiadiazepin-1,1-dione

To a mixture of zinc (28.5 g) and acetic acid (100 ml) was added thecompound prepared in reference example 27 (6.6 g) and the mixture wasstirred for 3 hours at 80° C. The mixture was filtered and the filtratewas concentrated. The resiue was washed with chloroform to give thetitle compound (1.10 g) having the following physical data.

TLC: Rf 0.60 (chloroform:methanol=9:1).

EXAMPLE 34

(2S)-N-[(3S)-1-(1,1-dioxo-(3H,4H,5H-benzo[f]-1,2,5-thiadiazepin-2-yl))-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

By the same procedure as described in example 14 using the compoundprepared in reference example 28 in place of the compound prepared inreference example 7, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.40 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.79 (dd, J=7.8, 1.2 Hz, 1H), 7.42-7.29 (m, 6H), 6.97 (t,J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.40 (brd, J=7.8 Hz, 1H), 5.10(m, 3H), 4.72 (m, 1H), 4.35 (br, 1H), 4.20 (m, 1H), 4.15 and 3.82 (eachd, J=7.8 Hz, each 1H), 3.80-3.35 (m, 4H), 1.80-1.38 (m, 6H)₁ 0 93 (d,J=6.3 Hz; 12H)

EXAMPLE 35-EXAMPLE 35(3)

By the same procedure as described in example 1->example 2->example 3using corresponding compounds, the compounds of the present inventionhaving the following physical data were obtained.

EXAMPLE 35

N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-(1R,2S)-2-benzoylaminocyclohexylcarboxamide

TLC: Rf 0.36 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.84 and 7.76 (each d, totally 2H), 7.58-7.38 (m, 3H),7.23 (m, 1H), 7.15-6.99 (m, 2H), 6.85-6.70 (m, 2H), 6.20-6.10 (m, 1H),4.82-4.65 (m, 1H), 4.38-4.20 (m, 1H), 3.92-3.80 (m, 2H), 3.51-3.38 (m,2H), 3.18-2.90 (m, 4H), 2.82-2.72 (m, 1H), 2.10-1.20 (m, 11H), 0.92-0.70(m, 6H).

EXAMPLE 35(1)

N-[5-methyl-2-oxo-1-(1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-(1R,2S)-2-benzoylaminocyclohexylcarboxamide

TLC: Rf 0.59 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.86-7.73 (m, 2H), 7.58-7.17 (m, 5H), 7.10-7.01 (m, 1H),6.94-6.80 (m, 2H), 6.21-6.11 (m, 1H), 4.82-4.67 (m, 1H), 4.37-4.22 (m,1H), 3.91-3.77 (m, 2H), 3.40-3.30 (m, 2H), 3.03-2.85 (m, 7H), 2.82-2.71(m, 1H), 2.20-1.23 (m, 11H), 1.05-0.73 (m, 6H).

EXAMPLE 35(2)

N-[5-methyl-2-oxo-1-(1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-(1R,2S)-2-(4-fluorobenzoylamino)cyclohexylcarboxamide

TLC: Rf 0.61 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.90-7.72 (m, 2H), 7.54 and 7.33 (each brd, J=7.8 Hz,total 1H), 7.29-7.17 (m, 1H), 7.14-7.02 (m, 3H), 6.96-6.80 (m, 2H), 6.17and 6.12 (each brd, J=7.8 Hz, total 1H), 4.83-4.68 (m, 1H), 4.32-4.20(m, 1H), 3.90-3.79 (m, 2H), 3.43-3.32 (m, 2H), 3.10-2.80 (m, 7H),2.78-2.69 (m, 1H), 2.13-1.20 (m, 11H), 1.08-0.73 (m, 6H)

EXAMPLE 35(3)

N-[(3S)-1-(1,1-dioxo-(3H,4H,5H-benzo[f]-1,2,5-thiadiazepin-2-yl))-5-methyl-2-oxo-3-hexyl]-(1R,2S)-2-benzoylaminocyclohexylcarboxamide

By the same procedure as described in example 1->example 2->example 3using the compound prepared in reference example 28 in place of1,3,4,5-tetrahydrobenzazepine, the title compound having the followingphysical data was obtained.

TLC: Rf 0.52 (ethyl acetate);

NMR (CDCl₃): δ 7.85-7.73 (m, 3H), 7.58-7.23 (m, 4H) 7.13 (brd, J=7.8 Hz,1H), 6.97 (t, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.14 (brd, J=7.4Hz, 1H), 4.79 (m, 1H), 4.42-4.23 (m, 2H), 4.15 and 3.92 (each d, J=18.0Hz, each 1H), 3.82-3.38 (m, 4H), 2.83-2.72 (m, 1H), 2.20-1.21 (m, 11H),0.82 (d, J=6.2 Hz, 6H).

FORMULATION EXAMPLE Formulation Example 1

The following components were admixed in a conventional method andpunched out to give 100 tablets each containing 50 mg of activeingredient.

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2- 5.0 gbenzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2- benzamidecyclohexyl]carboxamidecarboxymethylcellulose calcium(disintegrating agent) 0.2 g magnesiumstearate (lubricant) 0.1 g microcrystalline cellulose 4.7 g

Formulation Example 2

The following components were admixed in a conventional method. Thesolution was sterilized in conventional method, placed 5 ml portionsinto ampoules and freeze-dried in conventional method to give 100ampoules each containing 20 mg of the active ingredient.

N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2- 2.0 gbenzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2- benzamidecyclohexyl]carboxamidemannitol 20 g distilled water 500 ml

What is claimed is:
 1. A compound of formula (I-X),

wherein R is (i) hydrogen, (ii) C1-8 alkyl, (iii) CycA, (iv) C1-8 alkylsubstituted with a group selected from halogen atom, CycA, nitro, CF₃and cyano,

CycA is mono-, bi- or tri-cyclic C3-15 carboring or mono-, bi- ortri-cyclic 3-15 membered heteroring comprising 1-4 of nitrogen, 1-2 ofoxygen and/or 1 of sulfur; R¹⁶ is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3)C2-8 alkynyl, (4) CycA or (5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted with a group selected from halogen, nitro, CF₃, cyano, CycA,NR¹⁸R¹⁹ and —NHC(O)-CycA; R¹⁷, R¹⁸ and R¹⁹ each independently are,hydrogen or C1-4 alkyl, AA¹ is (i) a single bond, or

wherein R¹ and R² are the same or different and represent (i) hydrogen,(ii) C1-8 alkyl, (iii) CycA or (iv) C1-8 alkyl substituted with 1-5 ofgroup selected from the following (1)-(8): (1) —NR²¹R²², (2) —OR²³, (3)—SR²⁴, (4) —COR²⁵, (5) —NR²⁶CONR²¹R²², (6) guanidino, (7) CycA, (8)—NR²⁶SO₂R²¹; or R¹ and R² are taken together to form C2-8 alkylene,wherein one carbon atom may be replaced by oxygen, sulfur or —NR²⁰— andthe alkylene may be substituted with —NR²¹R²² or —OR²³, R²⁰ is hydrogen,C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkyl substituted withphenyl, R²¹, R²², R²³, R²⁴ and R²⁶ are the same or different andrepresent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted withphenyl, R²⁵ is C1-4 alkyl, phenyl, —NR²¹R²², wherein all symbols havethe same meanings as above, —OR²³, wherein R²³ is the same meaning asabove, or C1-4 alkyl substituted with phenyl, R³ is hydrogen, C1-8alkyl, phenyl or C1-8 alkyl substituted with phenyl or R³ is takentogether with R¹ to form C2-6 alkylene, wherein one carbon atom may bereplaced by oxygen, sulfur or —NR²⁰— and the alkylene may be substitutedwith —NR²¹R²² or —OR²³, or when AA¹ is

AA¹ and R may be taken together to form

 is a 5-12 membered mono- or bi-cyclic heteroring and the other symbolshave the same meanings as above, AA² is (i) a single bond,

wherein R⁴ and R⁵ are the same or different and represent (1) hydrogen,(2) C1-8 alkyl, (3) CycA or (4) C1-8 alkyl substituted with 1-5 of groupselected from the following (a)-(h): (a) —NR⁴¹ R⁴², (b) —OR⁴³, (c)—SR⁴⁴, (d) —COR⁴⁵, (e) —NR⁴⁶CONR⁴¹R⁴², (f) guanidino, (g) CycA, (h)—NR⁴⁶SO₂R⁴¹; or R⁴ and R⁵ are taken together to form C2-8 alkylenewherein one carbon atom may be replaced by oxygen, sulfur or —NR⁴⁰— andthe alkylene may be substituted with —NR⁴¹R⁴² or —OR⁴³, R⁴⁰ is hydrogen,C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkyl substituted withphenyl, R⁴¹, R⁴², R⁴³, R⁴⁴ and R⁴⁶ are the same or different andrepresent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted withphenyl, R⁴⁵ is C1-4 alkyl, phenyl, —NR⁴¹R⁴², wherein all symbols havethe same meaning as above, —OR⁴³, wherein R⁴³ has the same meaning asabove, or C1-4 alkyl substituted with phenyl, R⁶ is hydrogen, C1-8alkyl, phenyl or C1-8 alkyl substituted with phenyl or R⁶ is takentogether with R⁴ to form C2-6 alkylene, wherein one carbon atom may bereplaced by oxygen, sulfur or —NR⁴⁰— and the alkylene may be substitutedwith —NR⁴¹R⁴² or —OR⁴³, R⁴⁸ is hydrogen, C1-4 alkyl, phenyl or C1-4alkyl substituted with phenyl or when AA¹ is a single bond, R⁴⁸ and Rmay be taken together to form C2-6 alkylene, wherein one carbon atom maybe replaced by oxygen, sulfur or —NR⁴⁷—, wherein R⁴⁷ is hydrogen or C1-4alkyl, CycC is a 3-17 membered mono- or bi-cyclic heteroring, CycD is aC3-14 mono- or bi-cyclic carboring or a 3-14 membered mono- or bi-cyclicheteroring, or AA² and AA¹ are taken together to form

wherein CycE is a 4-18 membered mono- or bi-cyclic heteroring, CycF is a5-8 membered monocyclic heteroring, and the other symbols have the samemeanings as above, R⁷ and R⁸ are the same or different and represent (i)hydrogen, (ii) C1-8 alkyl, (iii) CycA or (iv) C1-8 alkyl substitutedwith 1-5 of group selected from the following (1)-(8); (1) —NR⁶¹R⁶², (2)—OR⁶³, (3) —SR⁶⁴, (4) —COR⁶⁵, (5) —NR⁶⁶CONR⁶¹R⁶², (6) guanidino, (7)CycA, (8)—NR⁶⁶SO₂R⁶¹, or R⁷ and R⁸ are taken together to form C2-8alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or—NR⁶⁰— and the alkylene may be substituted with —NR⁶¹R⁶² or —OR⁶³, R⁶⁰is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkylsubstituted with phenyl, R⁶¹, R⁶², R⁶³, R⁶⁴ and R⁶⁶ are the same ordifferent to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkylsubstituted with phenyl, R⁶⁵ is C1-4 alkyl, phenyl, —NR⁶¹R⁶², whereinall symbols have the same meanings as above, —OR⁶³, wherein R⁶³ has thesame meaning as above, or C1-4 alkyl substituted with phenyl, R⁹ ishydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl or R⁹is taken together with R⁷ to form C2-6 alkylene, wherein one carbon atommay be replaced by oxygen, sulfur or —NR⁶⁰— and the alkylene may besubstituted with —NR⁶¹R⁶² or —OR⁶³, q is an integer of 0 or 1 to 5, R¹⁰is (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) halogen,(v) CycA, (vi) —COR⁷¹, (vii) —NR⁷²R⁷³, (viii) —OR⁷⁴, or (ix) C1-8 alkyl,C2-8 alkenyl, C2-8 alkynyl substituted with 1-5 of group selected fromthe following <1>-<7>: <1> CycA, <2> guanidino, <3> —COR⁷¹, <4>—NR⁷²R⁷³, <5> —OR⁷⁴, <6> cyano and <7> —P(O)(OR⁸²)₂, wherein R⁸² ishydrogen, C1-8 alkyl, C1-4 alkyl substituted with 1-5 of phenyl, cyanoor halogen, R⁷¹ is (1) C1-8 alkyl, (2) CycA, (3) —NR⁷²R⁷³, (4) —OR⁷⁴ or(5) C1-8 alkyl substituted with CycA, R⁷² and R⁷³ are the same ordifferent and represent (1) hydrogen, (2) C1-8 alkyl, (3) CycA or (4)C1-8 alkyl substituted with 1-5 of group selected from the following(a)-(f): (a) CycA, (b) guanidino, (c) —NR⁷⁷R⁷⁸, wherein R⁷⁷ and R⁷⁸ arethe same or different and represent hydrogen, C1-4 alkyl, phenyl or C1-4alkyl substituted with phenyl, (d) —OR⁷⁷, wherein R⁷⁷ has the samemeaning as above, (e) —COR⁷⁶, wherein R⁷⁶ is C1-4 alkyl, phenyl,—NR⁷⁷R⁷⁸, wherein all symbols have the same meanings as above, —OR⁷⁷,wherein R⁷⁷ has the same meaning as above, or C1-4 alkyl substitutedwith phenyl, and (f) cyano; R⁷⁴ is (1) hydrogen, (2) C1-8 alkyl, (3)CycA, or (4) C1-8 alkyl substituted with 1-5 of groups selected from thefollowing (a)-(h), wherein one carbon atom may be replaced by oxygen,sulfur atom or —NR⁸⁴—; (a) CycA, (b) guanidino, (c) —SiR⁷⁹R⁸⁰R⁸¹,wherein R⁷⁹, R⁸⁰ and R⁸¹ are the same or different to represent, C1-8alkyl, phenyl or C1-8 alkyl substituted with phenyl, (d) —NR⁷⁷R⁷⁸,wherein all symbols have the same meanings as above, (e) —OR⁷⁷, whereinR⁷⁷ has the same meaning as above, (f) —COR⁷⁶, wherein R⁷⁶ has the samemeaning as above, (g) cyano, (h) —P(O)(OR⁸²)₂, wherein all symbols havethe same meanings as above; with the proviso that CycA in R, R¹, R², R⁴,R⁵, R⁷, R⁸, R¹⁰, R¹⁶, R⁷¹, R⁷², R⁷³, R⁷⁴, R⁸³ are the same or different,and CycA, CycB, CycC, CycD, CycE and CycF may be, each independently,substituted with 1-5 of R²⁷: R²⁷ is (1) C1-8 alkyl, (2) halogen, (3)—NR¹¹R¹², (4) —OR¹³, (5) C5-10 mono- or bi-cyclic carboring, (6) nitro,(7) CF₃, (8) cyano, (9) 5-10 membered mono- or bi-cyclic heteroring,(10) —SR¹⁴, (11) —COR¹⁵, (12) oxo, (13) —SO₂R¹⁵, (14) —OCF₃ or (15) C1-8alkyl substituted with 1-5 of group selected from the following (a)-(m):(a) halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) C5-10 mono- or bi-cycliccarboring, (e) nitro, (f) CF₃, (g) cyano, (h) 5-10 mono- or bi-cyclicheteroring, (j) —SR¹⁴, (k) —COR¹⁵, (l) —SO₂R¹⁵, (m) —OCF₃, wherein R¹¹and R¹² are the same or different and represent, hydrogen, C1-4 alkyl,—COO—(C1-4 alkyl), phenyl or C1-4 substituted with phenyl, R¹³ and R¹⁴are the same or different and represent, hydrogen, C1-4 alkyl, phenyl orC1-4 alkyl substituted with phenyl, R¹⁵ is C1-4 alkyl, phenyl, —NR¹¹R¹²,wherein all symbols have the same meanings as above, —OR¹³, wherein R¹³has the same meaning as above, or C1-4 alkyl substituted with phenyl, ora non-toxic salt thereof.
 2. The compound according to claim 1, whereinR is (i) hydrogen, (ii) C1-8 alkyl, (iii) CycA, (iv) C1-8 alkylsubstituted with CycA or nitro,

R¹⁶ is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) CycA, (5)C1-8 alkyl substituted with CycA or —NHC(O)-CycA, (6) C2-8 alkenylsubstituted with CycA, (7) C2-8 alkynyl substituted with CycA, AA¹ is(i) a single bond,

 or taken together with R to represent

wherein J¹ is oxygen, sulfur, —NR²⁹—, wherein R²⁹ is hydrogen, C1-4alkyl, CycA or C1-4 alkyl substituted with CycA, C1-3 alkylene or C2-3alkenylene, J² is a single bond or C1-2 alkylene, Y² is —N═CH—, —CH═N—or C1-2 alkylene, J³ is carbonyl or C1-3 alkylene, Y³ is C1-3 alkylene,oxygen or —NR²⁹—, wherein R²⁹ has the same meaning as above, R²⁸ ishydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with CycA, or R²⁸is taken together with R¹ to form C2-4 alkylene, and the other symbolshave the same meanings as defined in claim 1, each ring may besubstituted with 1-5 of R²⁷, AA² is (i) a single bond,

wherein J⁴, Y⁴, L⁴ are the same or different and represent a single bondor C1-3 alkylene, with the proviso that J⁴, Y⁴ and L⁴ do not represent asingle bond at the same time, J⁵ is C1-6 alkylene, Y⁵ is a single bond,C1-3alkylene or —NR⁶⁷—, wherein R⁶⁷ is hydrogen, C1-4 alkyl, phenyl orC1-4 alkyl substituted with phenyl, J⁸ is C1-5 alkylene, wherein onecarbon atom may be replaced by oxygen, Y⁸ is a single bond or C1-4alkylene, L⁸ is —N— or —CH—, J⁶ and Y⁶ are the same or different andrepresent a single bond or C1-3 alkylene, with the proviso that J⁶ andY⁶ do not represent a single bond at the same time, J⁷ is C1-6 alkylene,wherein one carbon atom may be replaced by oxygen, sulfur or —NR⁶⁷—,wherein R⁶⁷ has the same meaning as above, J⁹ is C1-3 alkylene, oxygen,sulfur or —NR⁶⁷—, wherein R⁶⁷ has the same meaning as above, and eachring may be substituted with 1-5 of R²⁷, or AA² and AA¹ are takentogether to form

wherein

 is a single bond or a double bond, J¹⁰ and Y¹⁰ are the same ordifferent and represent a single bond or C1-3 alkylene, L¹⁰ is a singlebond, C1-3alkylene, —NR⁵⁷—, wherein R⁵⁷ is hydrogen, C1-4 alkyl, phenylor C1-4 alkyl substituted with phenyl, —N═, oxygen or —S(O)_(p)—,wherein p is 0 or an integer of 1-2, J¹² and Y¹² are the same ordifferent and represent a single bond or C1-3 alkylene, L¹² is C1-3alkylene, —NR⁵⁷—, wherein R⁵⁷ has the same meaning as above, —N═, ═N—,oxygen or —S(O)_(p)—, wherein p has the same meaning as above, and theother symbols have the same meanings as defined in claim 1, and eachring may be substituted with 1-5 of R²⁷ and AA² and AA¹ are takentogether to form

wherein J¹¹ is carbonyl or C2-4 alkylene and the other symbols have thesame meanings as defined in claim 1, and R²⁷ in CycA is (1) C1-8 alkyl,(2) halogen, (3) —NR¹¹R¹², (4) —OR¹³, (5) phenyl, (6) nitro, (7) CF₃,(8) cyano, (9) tetrazole, (10) —SR¹⁴, (11) —COR¹⁵, (12) oxo, or (13)C1-8 alkyl substituted with 1-5 group selected from the following(a)-(k): (a) halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) phenyl, (e) nitro,(f) CF₃, (g) cyano, (h) tetrazole, (j) SR¹⁴, or (k) COR¹⁵, wherein allsymbols have the same meanings as above, and R¹⁰ is (i) C1-8 alkyl, (ii)CycA, (iii) —COR⁷¹ or (iv) C1-8 alkyl substituted with CycA, guanidino,—COR⁷¹, —NR⁷²R⁷³ or —OR⁷⁴, wherein all symbols have the same meanings asdefined in claim 1, or a non-toxic salt thereof.
 3. The compoundaccording to claim 2, wherein R is C1-8 alkyl, or C1-8 alkyl substitutedwith CycA or nitro,

and AA¹ is a single bond, or

and AA² is a single bond,


4. The compound according to claim 3, wherein R¹⁶ is C1-8 alkyl, C2-8alkenyl, C2-8 alkynyl, CycA or C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted with CycA, wherein CycA is mono- or bi-cyclic C5-10carboaryl or partially or completely saturated one thereof, or mono- orbi-cyclic 5-10 membered heteroaryl containing 1-2 of nitrogen, 1-2 ofoxygen and/or 1 of sulfur or partially or completely saturated onethereof, R¹ is hydrogen, C1-8 alkyl, phenyl, or C1-8 alkyl substitutedwith NH₂, C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂,guanidino, imidazole or indole and R² is hydrogen or R¹ and R² are takentogether to form C3-6 alkylene, R³ is hydrogen or C1-4 alkyl or R³ andR¹ are taken together to form C2-4 alkylene, AA² is a single bond,

R⁴ is hydrogen, C1-8 alkyl, phenyl, or C1-8 alkyl substituted with NH₂,C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole and R⁵ is hydrogen or R⁴ and R⁵ are taken togetherto form C3-6 alkylene, R⁶ is hydrogen or C1-4 alkyl or R⁶ and R⁴ aretaken together to form C2-4 alkylene, R⁴⁸ is hydrogen or C1-4 alkyl, R⁷is hydrogen, C1-8 alkyl, phenyl, or C1-8 alkyl substituted with NH₂,C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole and R⁸ is hydrogen or R⁷ and R⁸ are taken togetherto form C3-6 alkylene, R⁹ is hydrogen or C1-4 alkyl or R⁹ and R⁷ aretaken together to form C2-4 alkylene, or a non-toxic salt thereof. 5.The compound according to claim 1, wherein R¹⁶ is C1-8 alkyl, C2-8alkenyl or C2-8 alkynyl substituted with a group selected from halogen,nitro, CF₃′ cyano and NR¹⁸R¹⁹, or a non-toxic salt thereof.
 6. Thecompound according to claim 1, wherein R¹⁶ is (1) CycA containing 1-5 ofsubstituent R²⁷ or (2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted with CycA containing 1-5 of substituent R²⁷, wherein atleast one of R29 included in (1) and (2) is selected from (i) C5-10mono- or bi-cyclic carboring, (ii) 5-10 membered mono- or bi-cyclicheteroring, (iii) —SO₂R¹⁵, (iv) —OCF₃ and (v) C1-8 alkyl substitutedwith 1-5 of group selected from (a) halogen, (b) —NR¹¹R¹², (c) —OR¹³,(d) C5-10 mono- or bi-cyclic carboring, (e) nitro, (f) CF₃, (g) cyano,(h) 5-10 membered mono- or bi-cyclic heteroring, (j) —SR¹⁴, (k) —COR¹⁵,(1) —SO₂R¹⁵and (m) —OCF₃, wherein at least one substituent thereof isC5-10 mono- or bi-cyclic carboring, 5-10 membered mono- or bi-cyclicheteroring, —SO₂R¹⁵ and —OCF₃, or a non-toxic salt thereof.
 7. Acompound according to claim 1, wherein AA¹ is a single bond and R⁴⁸ andR are taken together to form C2-6 alkylene, wherein one carbon atom maybe replaced by —NR⁴⁷—, wherein R⁴⁷ is the same meaning as defined inclaim 1, oxygen or sulfur, or a non-toxic salt thereof.
 8. The compoundaccording to claim 1, wherein R¹⁰ is C2-8 alkenyl, C2-8 alkynyl or C2-8alkenyl or C2-8 alkynyl substituted with 1-5 of group selected fromCycA, guanidino, —COR⁷¹, —NR⁷²R⁷³, —OR⁷⁴, cyano and —P(O)(OR⁸²)₂, or anon-toxic salt thereof.
 9. A benzene-fused heteroring derivativeaccording to claim 1, which is (1)(3S)-3-(t-butoxycarbonylamino)-5-methyl-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2-hexanone,(2)(3S)-3-amino-5-methyl-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2-hexanone,(3)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[1×1R,2S)-2-benzamidecyclohexyl]carboxamide,(4)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-cyclohexylcarboxamide,(5)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide,(6)N-[(35)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(7)4-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(8)3-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(9)2-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(10)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]cinnamide,(11)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-3-cyclopentylpropanamide,(12)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(5-phenylimidazolidin-2,4-dion-3-yl)acetamide,(13)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(2-phenyl-1,6-dihydropyrimidin-6-on-1-yl)acetamide,(14)2-benzoylamino-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(15)(3S)-5-methyl-3-(2-methylpropoxycarbonylamino)-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)hexan-2-one,(16)(2S)-N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[1-phenethylpiperidin-2-yl]carboxamide,(17)(2S)-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,(18)(2S)-N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,(19)(2S)-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,(20)(ZR)-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,(21)1-cyclohexyl-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]carboxamide,(22)N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-3-cyclopentylpropanamide,(23)N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide,(24)N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2R)-2-benzoylaminocyclohexyl]carboxamide,(25)(2S)-N-[1-(2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)acetyl)cyclohexan-1-yl]-4-methyl-2-benzyloxycarbonylaminopentanamide,(26)(2S)-N-[1-(2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)acetyl)cyclohexan-1-yl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide,(27)N-[(35)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(1,3-diazaaspiro[4,5]decan-2,4-dione-3-yl)acetamide,(28)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(t-butoxycarbonylamino)cyclohexyl]carboxamide,(29)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-aminocyclohexyl]carboxamide,(30)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-chlorophenylcarbonylamino)cyclohexyl]carboxamide,(31)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-phenylacetylaminocyclohexyl]carboxamide,(32)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(IR,2S)-2-hydrocinnamoylaminocyclohexyl]carboxamide,(33)N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-acetylaminocyclohexyl]carboxamide,(34)N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(6-aminonicotinoyl)aminocyclohexyl]carboxamide,(35)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-(t-butoxycarbonyl)piperazin-1-ylcarbonylamino)cyclohexyl]carboxamide,(36)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(quinoxalin-2-ylcarbonylamino)cyclohexyl]carboxamide,(37)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-naphthoylaminocyclohexyl]carboxamide,(38)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-C1-benzothiophen-2-ylcarbonylamino)cyclohexyl]carboxamide,(39)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-C4-methoxybenzoylamino)cyclohexyl]carboxamide,(40)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-nitrobenzoylamino)cyclohexyl]carboxamide,(41)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-phenylbenzoylamino)cyclohexyl]carboxamide,(42)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]carboxamide,(43)N-[(3S)-5-methyl-2-oxo-1-C1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-pyridylcarbonylamino)cyclohexyl]carboxamide,(44)N-[(3S)-5-methyl-2-oxo-1-C1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-t-butylbenzoylamino)cyclohexyl]carboxamide,(45)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-methylthionicotinoylamino)cyclohexyl]carboxamide,(46)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(1-naphthylacetylamino)cyclohexyl]carboxamide,(47)N-[(3S)-5-methyl-2-oxo-1-C1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-fluorobenzoylamino)cyclohexyl]carboxamide,(48)N-[(3S)-1-(1,3,4,5-tetrahydro-2H-benzazepin-2-H-5-methyl-2-oxo-6-hexyl]-1-[(1R,2S)-2-(6-chloronicotinoylamino)cyclohexyl]carboxamide,(49)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-trifluoromethylbenzoylamino)cyclohexyl]carboxamide,(50)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]carboxamide,(51)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-methylbenzoylamino)cyclohexyl]carboxamide,(52)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-trifluoromethyloxybenzoylamino)cyclohexyl]carboxamide,(53)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(3-t-butyl-1-methylpyrazol-5-ylcarbonylamino)cyclohexyl]carboxamide,(54)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(N,N-di-n-propyl-4-sulfamoyl)benzoylamino]cyclohexyl]carboxamide,(55)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-mesylaminocyclohexyl]carboxamide,(56)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-phenylsulfonylaminocyclohexyl]carboxamide,(57)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-C4-dimethylaminobenzoylamino)cyclohexyl]carboxamide,(58)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(piperazin-1-ylcarbonylamino)cyclohexyl]carboxamide,(59)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzenesulfonamide,(60)1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone,(61)3-amino-1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-hexanone,(62)(2S)-N-[(3S)-1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,(63)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide,(64)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,25)-2-benzoylaminocyclohexyl]carboxamide,(65)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-cyclohexylcarboxamide,(66)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]benzamide,(67)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-3-cyclopentylpropanamide,(68)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-(2-benzyloxyphenyl)carboxamide,(69)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]cinnamide,(70)1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone,(71)1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-amino-5-methyl-2-hexanone,(72)(2S)-N-[1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,or (73)N-[1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide,or a non-toxic salt thereof.
 10. A composition comprising the compoundof formula (I-X) described in claim 1, or a non-toxic salt thereof, anda pharmaceutically acceptable carrier.
 11. A method for inhibitingcysteine protease comprising administering to a subject and effectiveamount of the compound of formula (I-X) described in claim 1, or anon-toxic salt thereof.
 12. The method according to claim 11, whereinsaid cysteine protease is cathepsin K, cathepsin S, cathepsin L,cathepsin B, cathepsin H, cathepsin or caspase-1.
 13. A method fortreatment of bone resorption diseases, comprising administering to asubject an effective amount of the compound of formula (I-X) describedin claim 1, or a non-toxic salt thereof.